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Classifications

NIH Highlighted Topic

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Inheritance

1

Autosomal dominant predisposition in a molecularly defined subset HP:0000006

Some familial cases have heterozygous pathogenic variants with age-dependent incomplete penetrance and variable ILD phenotype. Most IPF does not follow a single Mendelian pattern. Short telomeres can also be inherited without the familial variant, complicating recurrence prediction.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/ SUPPORT Other

"Each child of an individual with a ... associated with predisposition to pulmonary fibrosis has a 50% chance of inheriting the pathogenic variant."

The recurrence statement applies to autosomal dominant monogenic predisposition, not every sporadic IPF case; inheritance of a variant does not predict age of onset or guarantee disease.

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Mechanistic Hypotheses

3

Injury-Centric Wound Healing Model

injury_centric_model CANONICAL

Evidence balance 1 support

Repetitive alveolar epithelial injury is modeled as the primary upstream driver; AT2 cell senescence and subsequent fibroblast activation are downstream consequences of failed wound healing. Fibrosis represents an aberrant, non-resolving repair response to injury in genetically or environmentally susceptible individuals.

Retained as CANONICAL as a useful injury-and-aberrant-repair framework. Susceptibility, persistent signaling and regenerative failure can sustain fibrosis after an initiating insult; the framework does not require an identified recurrent exposure in every patient.

Show evidence (1 reference)

PMID:35563849 SUPPORT Other

"it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts."

Supports the injury-centric model in which repetitive microinjury is the upstream initiating event that leads to fibroblast activation.

Senescence-First (Stem-Cell Exhaustion) Model

senescence_first_model ALTERNATIVE

Evidence balance 9 support

AT2 senescence and loss of regenerative capacity may be proximal drivers of fibrosis, particularly in telomere-associated disease but also after other stress pathways. Human genetics and tissue studies support relevance; TRF1 and Sin3a mouse perturbations demonstrate spontaneous fibrosis, whereas other telomerase models require injury. Immune-cell-free organoids establish one epithelial-fibroblast route. The relative contributions of this route and immune amplification in human disease remain unresolved.

Retain ALTERNATIVE as a hypothesis about causal ordering, without assigning a validated exclusive patient subtype. OpenScientist provides useful multi-trigger and multi-cellular leads, but its universal second-hit and obligate-immune claims are rejected. Short leukocyte telomere frequencies do not define the fraction of IPF mediated by AT2 senescence. TERT deletion, telomere shortening and shelterin uncapping are distinct perturbations. The assessment records corrected source interpretation and missing declared artifacts.

Pathograph links

Alveolar epithelial telomere dysfunction -> AT2 cell senescence and SASP INDIRECT KNOWN INTERMEDIATES Telomere dysfunction activates a persistent DNA-damage response and senescence in AT2 cells.

Alveolar epithelial telomere dysfunction -> AT2 progenitor exhaustion and impaired alveolar regeneration INDIRECT KNOWN INTERMEDIATES Dysfunctional telomeres impair alveolar epithelial renewal; this contribution depends on the genetic and injury context.

Deep research

OpenScientist citations 41 citations 2026-07-06T08:51:02.976081

Show evidence (9 references)

PMID:37653024 SUPPORT In Vitro

"the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis."

Immune-cell-free organoids support an epithelial-fibroblast route in vitro, without proving whole-animal immune independence.

PMID:33808277 SUPPORT Other

"Loss of regenerative potential of alveolar type II epithelial cells (AT2) cells following injury has been postulated to underlie telomeropathy-associated lung fibrosis, with concomitant excessive proliferation of airway cells displaying abnormal phenotypes"

Review describes telomere-driven loss of AT2 regenerative capacity as a mechanistic explanation for the strong age and telomere-length associations in IPF.

PMID:33197388 SUPPORT Computational

"Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF"

Published Mendelian randomization supports a contribution of shorter telomeres to IPF susceptibility under instrumental-variable assumptions. The COPD comparator does not establish disease specificity across all conditions or AT2-specific causal timing.

+ 6 more references

Convergent Self-Sustaining Feedback Loop Model

feedback_loop_convergence_model ALTERNATIVE

Evidence balance 1 support

Epithelial stress, senescence, fibroblast persistence and matrix-derived mechanical signals may reinforce one another after initiation. Experimental TGF-beta and matrix-stiffness feedback support this convergent framework, but their relative necessity and therapeutic importance in human IPF remain unresolved.

This synthesis complements upstream injury and senescence hypotheses. Response to an antifibrotic drug does not by itself identify the initiating lesion or establish which feedback loop mediated benefit.

Pathograph links

Excessive extracellular matrix deposition -> Fibroblast activation and myofibroblast differentiation INDIRECT KNOWN INTERMEDIATES Matrix mechanical signals can reinforce fibroblast activation; the review supports a feedback framework without quantifying its necessity in humans.

Persistent epithelial and mesenchymal TGF-beta signaling -> AT2 cell senescence and SASP INDIRECT KNOWN INTERMEDIATES Autocrine TGF-beta sustains the profibrotic AT2-lineage state in the tested organoid model.

Show evidence (1 reference)

PMID:34813355 SUPPORT Other

"The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic),..."

Annual Review of Pathology review frames IPF as a convergence of multiple predisposing factors and cell types, consistent with the feedback loop model in which no single upstream event fully explains the disease.

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Discussions and Knowledge Gaps

4

Is repetitive alveolar epithelial injury the primary upstream driver of IPF, or does age-related AT2 cell senescence and telomere attrition precede and predispose to fibrosis independently of ongoing injury?

KNOWLEDGE GAP OPEN disc_ipf_injury_vs_senescence_ordering

Attached to

pathophysiology#AT2 cell senescence and SASP

Human disease likely combines epithelial susceptibility, injury and failed repair. TRF1 and Sin3a perturbations demonstrate spontaneous fibrosis in mice, while AT2-specific TERT loss and certain surfactant variants require additional injury. The unresolved question is how these distinct model-specific mechanisms map onto human causal ordering, not whether any spontaneous model exists.

Show evidence (2 references)

PMID:27699234 SUPPORT Model Organism

"These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis."

Conditional TRF1 deletion causes spontaneous fibrosis after prolonged epithelial telomere dysfunction; this severe uncapping model is distinct from ordinary age-related shortening.

PMID:32991815 SUPPORT Model Organism

"We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis."

An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin; it does not establish immune independence or the initiating lesion in all human IPF.

Which epithelial, mesenchymal and matrix-derived feedback processes sustain progressive IPF, how necessary are they in different patients, and which combinations are therapeutically tractable?

KNOWLEDGE GAP OPEN disc_ipf_ecm_feedback_irreversibility

Attached to

pathophysiology#Excessive extracellular matrix deposition pathophysiology#Aberrant basaloid cell emergence

Autocrine TGF-beta, matrix mechanics and persistent mesenchymal states can sustain experimental fibrosis. Human relative contributions and optimal combinations of interventions remain unresolved. Antifibrotic therapies slow FVC decline but do not establish reversal, while senolytic clinical studies remain small feasibility trials.

Does gut dysbiosis drive IPF progression (dysbiosis → fibrosis), or is it a secondary consequence of systemic inflammation and drug effects in established IPF (fibrosis → dysbiosis)? Are microbial metabolite deficits (SCFA, secondary bile acids) individually sufficient to amplify pulmonary fibrosis, or do they require cofactors? Can fecal microbiota transplantation attenuate pulmonary inflammation in human ILD?

KNOWLEDGE GAP OPEN disc_ipf_gut_lung_axis_causality

Attached to

pathophysiology#Gut dysbiosis and microbial metabolite dysregulation

The reviewed evidence combines clinical associations and preclinical gut-lung experiments. Directionality, specific microbial mediators, and independence from disease severity, diet and drug exposure remain unresolved. Human microbiome-directed therapeutic benefit is not established by the cited review.

Proposed experiments

Longitudinal microbiome profiling in IPF cohorts

exp_ipf_microbiome_temporal_cohort

Use longitudinal microbiome profiling with matched lung-function measures, diet, medication and severity covariates to assess temporal association. Temporal precedence alone does not establish causality.

Germ-free and antibiotic-depleted mouse IPF models

exp_ipf_germ_free_bleomycin

Germ-free or antibiotic-depleted mouse bleomycin models to test whether microbiota depletion attenuates pulmonary fibrosis, establishing a causal contribution of gut microbiota to lung fibrotic pathways.

SCFA supplementation in IPF mouse models

exp_ipf_scfa_supplementation

SCFA (butyrate and propionate) supplementation in bleomycin-induced pulmonary fibrosis mouse models to determine whether restoring microbial metabolite levels reduces fibrotic burden and pro-inflammatory cytokines.

Does MUC5B overexpression promote, protect against, or act independently of alveolar type II cell senescence? The two best-supported susceptibility mechanisms for sporadic IPF are expressed in the same epithelial cells but have not been studied in combination.

KNOWLEDGE GAP OPEN disc_ipf_muc5b_senescence_interaction

Attached to

genetic#MUC5B pathophysiology#Distal MUC5B overexpression and impaired clearance pathophysiology#AT2 cell senescence and SASP

The rs35705950 promoter variant is the strongest common genetic risk factor for sporadic IPF, and Hancock et al. report MUC5B co-expression with surfactant protein C in type 2 alveolar epithelium and in honeycomb-cyst epithelium (PMID:30560893), which places it in the same cells this entry models as senescent. The mechanism it is curated under, impaired distal mucociliary clearance, is not a senescence mechanism, and no study has asked whether MUC5B overexpression induces, protects against, or is orthogonal to AT2 senescence. If the two mechanisms are independent, risk should be close to additive and the mucociliary and senescence routes would describe partly different patients; if they interact, departure from additivity is expected. An OpenScientist report of the senescence-first model records PubMed searches for MUC5B with senescence and with telomere that returned no relevant studies, but commits no query log, so this is a reported absence rather than a documented one.

Proposed experiments

Co-expression of MUC5B and senescence markers in IPF tissue

exp_ipf_muc5b_senescence_coexpression

Quantify MUC5B alongside p16, p21 and senescence-associated beta-galactosidase in the same alveolar and honeycomb-cyst epithelial cells in IPF lung sections, stratified by rs35705950 genotype, to establish whether the mucin-high and senescent epithelial compartments are the same population or distinct ones.

Would support

pathophysiology#AT2 cell senescence and SASP

Supporting outcome

MUC5B-high alveolar epithelial cells are enriched for senescence markers relative to MUC5B-low cells from the same lungs, indicating that the mucociliary susceptibility route feeds the senescence node rather than bypassing it.

Refuting outcome

MUC5B-high and senescence-marker-high epithelial cells occupy separate, non-overlapping compartments, which would be consistent with two routes to fibrosis acting in different cells or different patients.

MUC5B genotype by telomere length interaction in an IPF cohort

exp_ipf_muc5b_telomere_epistasis

In an IPF cohort powered for an interaction term, genotype rs35705950, measure leukocyte telomere length, and fit additive and multiplicative interaction models for FVC decline and transplant-free survival. Leukocyte telomere length is an imperfect proxy for alveolar epithelial senescence, so a null interaction would not by itself exclude convergence in the lung.

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Pathophysiology

21

Repetitive alveolar epithelial injury and aberrant repair

Recurrent injury to alveolar epithelial cells, particularly type II pneumocytes, initiates a dysregulated wound-healing response that fails to restore normal alveolar architecture and instead drives fibrotic remodeling.

type II pneumocyte CL:0002063

wound healing GO:0042060 ↕ DYSREGULATED apoptotic process GO:0006915 ↑ INCREASED

lung UBERON:0002048

Downstream

AT2 cell senescence and SASP Bleomycin-induced DNA damage activates p53 and a senescent transitional epithelial state.

Profibrotic macrophage recruitment and amplification Injured epithelium produces CCR2 ligands that promote exudate macrophage recruitment in a mouse injury model.

Self-DNA sensing through epithelial cGAS DNA-damaging epithelial stress increases mitochondrial DNA in cytosolic and extracellular compartments in primary cultures.

Show evidence (2 references)

PMID:35563849 SUPPORT Other

"it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts."

This review directly supports repetitive epithelial injury as the initiating trigger for maladaptive wound healing in IPF.

PMID:33201251 SUPPORT Other

"Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling."

This review links epithelial apoptosis and senescence to the abnormal remodeling response after lung injury in IPF.

AT2 cell senescence and SASP

AT2-lineage cells can enter a stress-associated senescent state with reduced regenerative capacity and a secretory program that activates fibroblasts. DNA damage, telomere dysfunction, chronic Wnt signaling and metabolic stress are candidate upstream routes. Bleomycin-treated epithelial-fibroblast organoids show autocrine TGF-beta feedback and paracrine myofibroblast induction without immune cells. In vivo models establish senescence as a possible proximal driver, while the contribution of immune recruitment varies by model and cannot be declared universally necessary or dispensable.

type II pneumocyte CL:0002063

cellular senescence GO:0090398 ↑ INCREASED TGF-beta receptor signaling pathway GO:0007179 ↑ INCREASED

lung UBERON:0002048

Experimental models

Immune-cell-free AT2-lineage and fibroblast organoids ORGANOID Bleomycin-induced DNA damage activates p53 and a profibrotic secretory epithelial state.

Animal models

AT2-specific Sin3a conditional loss Mus musculus perturbs Conditional Sin3a loss induces p53-dependent senescence, AT2 depletion and spontaneous fibrosis.

AT2-specific TERT conditional deletion with bleomycin Mus musculus perturbs TERT deficiency heightens senescence and impairs regeneration after injury.

Downstream

Persistent epithelial and mesenchymal TGF-beta signaling Senescent profibrotic AT2-lineage cells produce TGF-beta in the organoid system.

AT2 progenitor exhaustion and impaired alveolar regeneration Senescence impairs epithelial regeneration and produces AT2 depletion in the Sin3a perturbation model.

Show evidence (3 references)

PMID:37653024 SUPPORT In Vitro

"bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast..."

The immune-cell-free organoid experiment establishes epithelial-fibroblast sufficiency under bleomycin stimulation; accompanying mouse genetics do not imply immune independence of whole-animal disease.

PMID:34813355 SUPPORT Other

"Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair."

Annual Review of Pathology 2022 review places AT2 senescence as a consequence of recurrent injury that bridges injury to downstream fibrotic mechanisms.

PMID:32991815 SUPPORT Model Organism

"We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis."

An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin; it does not establish immune independence or the initiating lesion in all human IPF.

Alveolar epithelial telomere dysfunction

Pathogenic telomere-maintenance variants and age-related shortening can produce dysfunctional telomeres and persistent DNA-damage signaling in alveolar epithelial cells. The human genetic evidence supports susceptibility, with incomplete penetrance. Experimental shelterin/TRF1 uncapping can induce spontaneous lung fibrosis, whereas AT2-specific TERT loss increases bleomycin susceptibility without measurable telomere shortening in one model. These perturbations must not be treated as interchangeable demonstrations of physiological telomere attrition.

Senescence-First (Stem-Cell Exhaustion) Model

type II pneumocyte CL:0002063

TERT hgnc:11730 TERC hgnc:11727 RTEL1 hgnc:15888 PARN hgnc:8609

telomere maintenance GO:0000723 ↓ DECREASED DNA damage response GO:0006974 ↑ INCREASED

lung UBERON:0002048

Animal models

AT2-specific TRF1 conditional deletion Mus musculus perturbs TRF1 loss perturbs telomere protection and eventually shortens telomeres.

Downstream

AT2 cell senescence and SASP Telomere dysfunction activates a persistent DNA-damage response and senescence in AT2 cells.

AT2 progenitor exhaustion and impaired alveolar regeneration Dysfunctional telomeres impair alveolar epithelial renewal; this contribution depends on the genetic and injury context.

Show evidence (4 references)

PMID:17392301 SUPPORT Human Clinical

"Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres."

The familial cohort demonstrates pathogenic telomerase variants and short telomeres. Unaffected carriers also had short telomeres, showing incomplete disease penetrance.

PMID:27699234 SUPPORT Model Organism

"These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing cells, leads to age-dependent lung remodeling and fibrosis."

Conditional TRF1 deletion causes spontaneous fibrosis after prolonged epithelial telomere dysfunction; this severe uncapping model is distinct from ordinary age-related shortening.

PMID:25848748 SUPPORT Human Clinical

"PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members."

Human pedigrees link rare variants to telomere dysfunction and familial pulmonary fibrosis.

+ 1 more reference

AT2 progenitor exhaustion and impaired alveolar regeneration

AT2 cells normally regenerate the alveolar epithelium. Senescence and telomere dysfunction impair renewal and can deplete functional progenitors. Cell loss and a persistent senescent secretory state are distinct mechanisms: the Sin3a model distinguishes progressive senescence-associated fibrosis from transient remodeling after AT2 ablation.

type II pneumocyte CL:0002063

stem cell population maintenance GO:0019827 ↓ DECREASED tissue regeneration GO:0042246 ↓ DECREASED

lung UBERON:0002048

Downstream

Architectural distortion and gas-exchange failure Persistent failure of epithelial restoration contributes to progressive remodeling; simple cell ablation alone need not cause progressive fibrosis.

Show evidence (2 references)

PMID:18753630 SUPPORT Human Clinical

"Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase components, hTERT and hTR, underlie inheritance in a subset of families with IPF."

Establishes that short telomeres limit lung tissue-renewal capacity, supporting exhaustion of the alveolar type II progenitor pool. Evidence source is HUMAN_CLINICAL (patient telomere-length study).

PMID:32991815 SUPPORT Model Organism

"We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation or senescence block fibrogenesis."

Senescence-associated dysfunction cannot be reduced to simple progenitor depletion.

Aberrant basaloid cell emergence

KRT5-negative/KRT17-positive aberrant basaloid epithelial cells coexpress basal, mesenchymal and senescence-related markers and occur near myofibroblast foci in fibrotic human lungs. Their transcriptome is a disease-associated state rather than proof of epithelial conversion into fibroblasts. Human AT2 cultures can undergo a basal transition under defined signaling conditions, but the origin and causal contribution of every basaloid cell population in human IPF remain unresolved.

aberrant basaloid epithelial cell CL:0000646

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED cellular senescence GO:0090398 ↑ INCREASED

lung UBERON:0002048

Show evidence (5 references)

PMID:33859634 SUPPORT Human Clinical

"Within both the IPF and SSc-ILD samples we identified a small population of the recently described aberrant basaloid cells (or KRT5-/KRT17+ cells), with no cells sharing this distinct transcriptome amongst the control samples"

Human single-cell data identify this population in both IPF and SSc-ILD, so it is not specific to IPF and does not establish senescence-to-basaloid lineage causality.

PMID:34813355 SUPPORT Other

"These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell, which may disrupt normal epithelial repair and propagate a profibrotic phenotype."

Annual Review of Pathology 2022 review identifies the aberrant basaloid cell population as mechanistically relevant to IPF pathogenesis through disruption of normal epithelial repair.

PMID:32832599 SUPPORT Human Clinical

"Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung."

Single-cell and histologic localization demonstrate a disease-associated state, not causal lineage conversion.

+ 2 more references

Epithelial and endothelial mesenchymal drift

Lung epithelial and endothelial cells in IPF lose lineage identity and up-regulate a mesenchymal gene program, the age-associated mesenchymal drift signature. In single-cell data this appears both as a shift in cell-type composition and as reprogramming within individual epithelial and endothelial cells, and a higher drift score in bronchoalveolar lavage tracks shorter survival. The signature is defined transcriptomically; whether the KRT17-positive aberrant basaloid population is one form of this drift or a separate injury-driven state is not established, so no edge links the two nodes.

lung epithelial cell CL:0000066 lung endothelial cell CL:0000115

mesenchymal drift (aberrant acquisition of mesenchymal identity) GO:0048762 ⚠ ABNORMAL

lung UBERON:0002048

Downstream

Excessive extracellular matrix deposition Cells drifting toward a mesenchymal state express extracellular-matrix and profibrotic programs that add to the fibrotic matrix.

Show evidence (2 references)

PMID:41322283 SUPPORT REVIEW SYNTHESIS Human Clinical

"In idiopathic pulmonary fibrosis (IPF), single-cell analyses reveal both compositional shifts and within-cell reprogramming of epithelial and endothelial populations."

Review summary of the IPF single-cell results in Lu et al. 2025 (PMID:40816266), whose abstract does not itemize diseases. Graded HUMAN_CLINICAL for the human single-cell data it describes; the quote is the review's synthesis, not its own result.

PMID:41322283 SUPPORT REVIEW SYNTHESIS Human Clinical

"In a complementary bronchoalveolar lavage (BAL) gene-expression cohort of IPF patients (n = 132), stratification by MD-gene levels yielded median survival times of 2,498, 1,027/604, and 59 days across low, middle, and high MD groups, respectively"

Associates a higher drift score with shorter survival in an IPF cohort. This is a correlation and does not show that the drift causes progression.

Gut dysbiosis and microbial metabolite dysregulation

Mechanism confidence: Hypothetical

Altered gut microbial composition and metabolites have been associated with interstitial lung disease, and preclinical models suggest effects on immune responses and fibrosis. Directionality, specific mediators and independence from diet, disease severity and antifibrotic treatment remain unresolved in human IPF. This is an emerging modifier rather than an established universal upstream mechanism.

large intestine UBERON:0000059 lung UBERON:0002048

Show evidence (2 references)

PMID:42294946 SUPPORT Other

"Accumulating evidence supports bidirectional gut-lung axis interactions potentially mediated by the microbiota. Alterations in the gut microbiome have been associated with the onset and severity of interstitial lung disease."

Review-level evidence summarizes clinical associations and preclinical gut-lung mechanisms; it does not establish the specified causal sequence or direction in human IPF.

PMID:42294946 SUPPORT Other

"Preclinical studies demonstrate that gut dysbiosis is associated with altered immune responses, increased pro-inflammatory cytokines, and enhanced fibrotic pathways, with mechanistic evidence suggesting the involvement of specific microbial metabolites (short-chain fatty acids, bile acids, and..."

Review-level evidence summarizes clinical associations and preclinical gut-lung mechanisms; it does not establish the specified causal sequence or direction in human IPF.

Profibrotic macrophage recruitment and amplification

Recruited monocyte-derived macrophages can amplify fibrosis after epithelial injury through CCR2-dependent pathways. Macrophage behavior changes with cell state and disease phase: some macrophage-derived signals promote resolution and fibroblast apoptosis. Neither a uniformly profibrotic macrophage role nor universal immune dependence follows from these models.

alveolar macrophage CL:0000583

inflammatory response GO:0006954 ↑ INCREASED leukocyte migration GO:0050900 ↑ INCREASED

lung UBERON:0002048

Downstream

Excessive extracellular matrix deposition Bone-marrow-derived monocyte recruitment contributes to enhanced collagen deposition after bleomycin; the effect is model- and cell-state-dependent.

Show evidence (2 references)

PMID:31922885 SUPPORT Model Organism

"In contrast, mice with lung epithelial cell-specific deletion of CCL12 were protected from bleomycin-induced fibrosis and had expression of CCL2 and CCL7 similar to that of control mice treated with bleomycin. Deletion of CCL12 within AECs led to decreased recruitment of exudate macrophages."

Epithelial CCL12 contributes to macrophage recruitment in this mouse injury model; global CCL12 deletion was not protective and this is not universal immune necessity.

PMID:34386777 SUPPORT Model Organism

"Together, these findings reveal a novel role of SIRT3 in pro-resolution macrophage functions that restore susceptibility to apoptosis in fibroblasts via a FoxO3a-dependent mechanism."

Macrophage-dependent effects can also favor resolution in the SIRT3 restoration model.

IL-11 Autocrine Signalling in Lung Fibroblasts

Mechanism confidence: Provisional

IL-11 is increased in human IPF lungs and secreted by IPF fibroblasts. In cultured lung fibroblasts it promotes ERK-dependent, posttranscriptional myofibroblast conversion. Neutralizing IL-11 reverses fibrosis in a mouse model; efficacy in human IPF is not established by that experiment.

lung fibroblast CL:0002553

Interleukin-11-mediated signaling pathway GO:0038154 ↑ INCREASED ERK1 and ERK2 cascade GO:0070371 ↑ INCREASED

lung UBERON:0002048

Downstream

Fibroblast activation and myofibroblast differentiation IL-11 activates ERK-dependent myofibroblast conversion and collagen secretion.

Show evidence (3 references)

PMID:31554736 SUPPORT Human Clinical

"interleukin-11 (IL11) is up-regulated in the lung of patients with IPF, associated with disease severity, and IL-11 is secreted from IPF fibroblasts"

Establishes IL-11 up-regulation in patient IPF lung and its secretion by IPF fibroblasts, grounding this node in human disease. Evidence source is HUMAN_CLINICAL (patient lung tissue).

PMID:31554736 SUPPORT In Vitro

"IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2+), collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional manner"

Directly evidences the IL-11 to ERK receptor-signalling arm driving fibroblast-to-myofibroblast conversion modeled by this node. Evidence source is IN_VITRO (cultured lung fibroblasts).

PMID:31554736 SUPPORT Model Organism

"anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK and SMAD activation in mice"

Shows pharmacological IL-11 inhibition reverses lung fibrosis and lowers ERK activation in vivo, validating the drug-target link on this node. Evidence source is MODEL_ORGANISM (bleomycin mouse model).

Fibroblast activation and myofibroblast differentiation

Resident mesenchymal cells become matrix-producing myofibroblasts in response to profibrotic mediators including TGF-beta and IL-11 and mechanical signals from matrix. Epithelial plasticity can alter the signaling environment, but coexpression of mesenchymal markers does not establish that epithelial cells are the source of pathogenic fibroblasts.

fibroblast CL:0000057 myofibroblast CL:0000186

TGF-beta receptor signaling GO:0007179 ↑ INCREASED

lung UBERON:0002048

Experimental models

Microengineered alveolar array lung-on-chip with breathing mechanics ORGAN ON CHIP Cyclic stretch applied together with TGF-beta 1 amplified fibrotic signalling well beyond TGF-beta 1 alone. This makes breathing motion an explicit cofactor of fibroblast activation rather than background, which is the mechanistic claim a static culture cannot test.

Downstream

Excessive extracellular matrix deposition Activated myofibroblasts synthesize collagen and other matrix proteins.

Show evidence (2 references)

PMID:35563849 SUPPORT Other

"it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response, during which fibroblasts differentiate into myofibroblasts."

This review directly supports fibroblast-to-myofibroblast differentiation as a core transition downstream of epithelial injury.

PMID:32549377 SUPPORT Other

"TGF-β is a critical cytokine that drives development of fibrosis."

This review supports TGF-beta signaling as a central profibrotic pathway in IPF.

Excessive extracellular matrix deposition

Persistent matrix-producing mesenchymal cells deposit collagen and other extracellular matrix components. Progressive scarring stiffens and distorts the lung. Matrix-derived mechanical signals can reinforce fibroblast activation, without proving an irreversible autonomous scar state in every patient.

Convergent Self-Sustaining Feedback Loop Model

myofibroblast CL:0000186

extracellular matrix organization GO:0030198 ↑ INCREASED collagen biosynthetic process GO:0032964 ↑ INCREASED

lung UBERON:0002048

Experimental models

Microengineered alveolar array lung-on-chip with breathing mechanics ORGAN ON CHIP Matrix protein and PAI-1 expression rose under profibrotic stimulation and fell with nintedanib, an approved IPF antifibrotic, giving the model pharmacological validation against the standard of care for this node.

Animal models

AT2-specific TRF1 conditional deletion Mus musculus recapitulates Collagen deposition increases after prolonged epithelial telomere dysfunction.

Downstream

Architectural distortion and gas-exchange failure Interstitial scarring disrupts architecture and gas exchange and decreases compliance.

Fibroblast activation and myofibroblast differentiation Matrix mechanical signals can reinforce fibroblast activation; the review supports a feedback framework without quantifying its necessity in humans.

Show evidence (2 references)

PMID:32549377 SUPPORT Other

"changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis."

This review links activated myofibroblasts directly to ECM deposition, architectural remodeling, and fibrosis in IPF.

PMID:38232990 SUPPORT Other

"Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact dynamically through multiple signalling pathways, including biochemical/molecular and mechanical signals, such as stiffness, affecting cell function and differentiation."

Supports the mechano-transduction concept: matrix stiffness signals through integrin pathways to maintain fibroblast activation independently of soluble TGF-beta, providing a mechanistic basis for the feedback edge from ECM deposition back to fibroblast activation.

Architectural distortion and gas-exchange failure

Progressive interstitial scarring distorts alveolar units, decreases lung compliance and increases elastic recoil. Restricted lung expansion, loss of functioning alveolar-capillary surface and impaired oxygen transfer produce exertional limitation, hypoxemia and ultimately respiratory failure.

lung UBERON:0002048

Downstream

Dyspnea Reduced compliance and impaired gas exchange increase the burden of exertion and breathlessness.

Exercise intolerance Fibrotic physiologic impairment limits exercise capacity.

Hypoxemia Disrupted alveolar-capillary gas exchange impairs oxygenation.

Respiratory failure Advanced architectural destruction produces severe gas-exchange failure.

Hypoxic pulmonary vasoconstriction and vascular remodeling Impaired ventilation and hypoxic alveolar regions can trigger compensatory vasoconstriction with maladaptive consequences when persistent.

Show evidence (1 reference)

PMID:32549377 SUPPORT Other

"The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory failure and death."

This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.

Distal MUC5B overexpression and impaired clearance

Mechanism confidence: Provisional

The common MUC5B promoter risk allele increases pulmonary expression. Distal-airspace MUC5B overexpression impairs clearance and worsens persistent fibrosis after bleomycin in mice. This supplies a genetic susceptibility route distinct from telomere dysfunction; interaction with short leukocyte telomeres has been studied epidemiologically but its cellular mechanism remains unresolved.

MUC5B hgnc:7516

lung UBERON:0002048

Downstream

Excessive extracellular matrix deposition Impaired distal clearance increases the extent and persistence of fibrosis after epithelial injury; the intervening injury and repair steps are not resolved by the human association.

Show evidence (2 references)

PMID:21506741 SUPPORT Human Clinical

"A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis."

This human case-control study identifies the MUC5B promoter variant rs35705950 as a major inherited susceptibility factor for IPF.

PMID:30560893 SUPPORT Model Organism

"In mice, we demonstrate that Muc5b concentration in bronchoalveolar epithelia is related to impaired mucociliary clearance (MCC) and to the extent and persistence of bleomycin-induced lung fibrosis."

Muc5b overexpression is a susceptibility amplifier in an injury model, not proof that this allele alone initiates fibrosis in humans.

Surfactant dysfunction and epithelial proteostasis stress

Rare surfactant variants predispose a subset of familial interstitial lung disease, sometimes classified as IPF. Misprocessing and endoplasmic-reticulum stress can compromise AT2 function, but variants differ: SP-A1 R219W-driven TGF-beta secretion is UPR dependent, whereas SP-C I73T and M71V secretion is largely UPR independent. L188Q SFTPC-induced ER stress increases bleomycin susceptibility without spontaneous fibrosis in one mouse model. Herpesvirus colocalization with UPR markers in human tissue does not establish viral causation.

type II pneumocyte CL:0002063

SFTPC hgnc:10802 SFTPA1 hgnc:10798 SFTPA2 hgnc:10799

lung UBERON:0002048

Downstream

Repetitive alveolar epithelial injury and aberrant repair Variant-specific proteostasis stress sensitizes alveolar epithelium to injury and aberrant repair.

Persistent epithelial and mesenchymal TGF-beta signaling Variant expression increases secretion of latent TGF-beta in epithelial cell lines; dependence on the unfolded protein response differs by variant.

Show evidence (4 references)

PMID:23926107 SUPPORT In Vitro

"We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines."

Surfactant variants can promote TGF-beta secretion through variant-dependent pathways.

PMID:21670280 SUPPORT Model Organism

"Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis was identified in the absence of a second profibrotic stimulus."

The second-hit requirement is specific to this mutant-surfactant model.

PMID:18390830 SUPPORT Human Clinical

"ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could contribute to disease progression."

Human tissue supports pathway presence; the conditional language is retained.

+ 1 more reference

Chronic canonical Wnt activation

Mechanism confidence: Provisional

Persistent canonical WNT/beta-catenin activation can shift AT2 cells toward senescence and impaired progenitor behavior in cultures and precision-cut lung slices. Acute and chronic stimulation differ. WNT5A did not reproduce the canonical senescence response in the cited assay; this does not exclude other profibrotic WNT5A actions.

type II pneumocyte CL:0002063

lung UBERON:0002048

Downstream

AT2 cell senescence and SASP Sustained canonical Wnt stimulation induces senescence in alveolar epithelial models.

Show evidence (2 references)

PMID:32109549 SUPPORT In Vitro

"Chronic canonical WNT/β-catenin activation for up to 7 days in primary ATII cells as well as alveolar epithelial cell lines induced a robust cellular senescence, whereas the non-canonical ligand WNT5A was not able to induce cellular senescence."

Sustained canonical signaling induces senescence in these cultures; telomere independence was not directly tested.

PMID:12707032 SUPPORT Human Clinical

"In 18 of 20 cases of IPF/UIP investigated on serial sections, nuclear beta-catenin immunoreactivity and abnormal levels of cyclin-D1 and matrilysin were demonstrated in proliferative bronchiolar lesions (basal-cell hyperplasia, squamous metaplasia, bronchiolization, honeycombing)"

Immunohistochemistry places the pathway readout, nuclear beta-catenin with induction of the targets cyclin-D1 and matrilysin, in human IPF/UIP tissue, and the same study reports these features absent from normal lung and from other fibrosing pneumonias. It localizes activation to proliferative bronchiolar and honeycomb lesions rather than to alveolar type II cells specifically, so it grounds the node in the human disease without establishing the AT2 route tested in culture.

AT2 fatty-acid oxidation impairment

Mechanism confidence: Provisional

FAO gene expression is reduced in human IPF alveolar epithelium. Experimental CPT1a deficiency produces mitochondrial dysfunction, lower SMAD7 and increased TGF-beta signaling, abnormal epithelial intermediates and increased injury susceptibility. These findings support a metabolic contribution to abnormal repair without proving that FAO loss is the initiating event in human IPF.

type II pneumocyte CL:0002063

CPT1A hgnc:2328

lung UBERON:0002048

Downstream

Aberrant basaloid cell emergence Metabolic perturbation promotes aberrant intermediate states bearing basaloid markers; these markers do not establish identity with every human basaloid population.

AT2 cell senescence and SASP AT2 CPT1a deficiency increases senescence-marker-positive epithelial cells during experimental fibrosis.

Show evidence (2 references)

PMID:39927460 SUPPORT In Vitro

"Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2."

CPT1a perturbation changes epithelial metabolism and cell states in experimental models.

PMID:39927460 SUPPORT Model Organism

"Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence."

AT2-specific metabolic deficiency amplifies injury-associated fibrosis; it is not an established monogenic cause of human IPF.

Self-DNA sensing through epithelial cGAS

Mechanism confidence: Provisional

Mitochondrial DNA accumulation in cytosol and extracellular medium accompanies stressed IPF epithelial cultures. cGAS inhibition, RNA interference and DNase experiments support self-DNA-dependent senescence amplification. The study does not demonstrate obligatory STING activation or a requirement for recruited immune cells in every fibrosis model.

type II pneumocyte CL:0002063

CGAS hgnc:21367

lung UBERON:0002048

Downstream

AT2 cell senescence and SASP Self-DNA sensing augments epithelial senescence in primary cultures and cell-line perturbations.

Show evidence (1 reference)

PMID:34524912 SUPPORT In Vitro

"Furthermore, ectopic mtDNA augmented cGAS-dependent senescence of Ctrl-AECs, whereas DNAse I treatment diminished IPF-AEC senescence."

Self-DNA perturbations and cGAS inhibition support senescence amplification in cultured epithelial cells.

Persistent epithelial and mesenchymal TGF-beta signaling

Epithelial and mesenchymal TGF-beta signaling promotes myofibroblast differentiation and dysplastic epithelial repair. In a bleomycin-exposed organoid system an epithelial autocrine loop sustains a profibrotic secretory state. Sustained signaling also redirects human AT2 repair toward basaloid intermediates; this is distinct from epithelial conversion into fibroblasts.

Convergent Self-Sustaining Feedback Loop Model

type II pneumocyte CL:0002063

lung UBERON:0002048

Downstream

AT2 cell senescence and SASP Autocrine TGF-beta sustains the profibrotic AT2-lineage state in the tested organoid model.

Fibroblast activation and myofibroblast differentiation Paracrine epithelial TGF-beta induces myofibroblast differentiation.

Aberrant basaloid cell emergence Persistent TGF-beta/SMAD3 signaling promotes dysplastic transitional-cell programs, including KRT17 and stratifin.

Show evidence (2 references)

PMID:37653024 SUPPORT In Vitro

"Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation."

Within the tested organoid system, epithelial TGF-beta mediates fibroblast differentiation; the exclusivity is assay-specific.

PMID:37653024 SUPPORT In Vitro

"Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis."

Perturbations in immune-cell-free epithelial-fibroblast organoids support a local autocrine loop.

Senescent myofibroblast persistence and apoptosis resistance

Aging-associated myofibroblasts can fail to dedifferentiate and become resistant to apoptosis. NOX4/NRF2 redox imbalance, sustained MyoD and BCL-2-dependent survival support persistence in experimental systems. Human IPF fibroblasts share aspects of these states. Senescence therefore contributes through mesenchymal persistence as well as epithelial dysfunction.

lung UBERON:0002048

Downstream

Excessive extracellular matrix deposition Failure of myofibroblast clearance maintains matrix-producing cells and persistent fibrotic remodeling.

Show evidence (3 references)

PMID:41764163 SUPPORT Model Organism

"Here, we show that prevention of PDGFRα+ fibroblast apoptosis by conditional BCL-2 expression leads to the emergence and persistence of senescent, pro-fibrotic fibroblasts along with enduring, pathologic fibrotic lung remodeling."

Conditional anti-apoptotic signaling demonstrates a fibroblast persistence route in mice, not universal BCL-2 dependence in humans.

PMID:31962055 SUPPORT In Vitro

"We demonstrated that nonsenescent lung myofibroblasts maintained the capacity for dedifferentiation, whereas senescent/IPF myofibroblasts exhibited an impaired capacity for dedifferentiation."

Cultured IPF fibroblasts show impaired fate reversal.

PMID:24718857 SUPPORT In Vitro

"Nox4 mediated senescence and apoptosis resistance in IPF fibroblasts."

Experimental fibroblast perturbations support redox-dependent persistence.

Age-associated endothelial repair failure

Mechanism confidence: Provisional

Endothelial ERG dysregulation and capillary cell-state changes accompany aging and fibrotic repair. Conditional endothelial ERG loss impairs fibrosis resolution in mice and enhances paracrine fibroblast activation in culture. Human transcriptional overlap supports relevance but does not establish an independent initiating vascular lesion in all IPF.

lung UBERON:0002048

Downstream

Fibroblast activation and myofibroblast differentiation Loss of endothelial ERG enhances paracrine fibroblast activation in culture.

Show evidence (1 reference)

PMID:35879310 SUPPORT Model Organism

"Loss of endothelial ERG ... impairs lung fibrosis resolution in young mice in vivo."

Conditional endothelial ERG loss impairs fibrosis resolution in mice; the separate in-vitro edge quotes the fibroblast-activation finding.

Hypoxic pulmonary vasoconstriction and vascular remodeling

Disturbed ventilation-perfusion and alveolar hypoxia can provoke pulmonary vasoconstriction. Persistent vasoconstriction and vascular remodeling contribute to pulmonary hypertension, alongside cytokine and growth-factor effects. Pulmonary hypertension severity is not determined solely by the extent of fibrosis.

lung UBERON:0002048

Downstream

Pulmonary hypertension Sustained vascular constriction and remodeling increase pulmonary vascular resistance and pressure.

Show evidence (1 reference)

PMID:31423872 SUPPORT Other

"However, continuous HPV‐related vasoconstriction can induce shear stress–related vascular remodeling"

The review describes a pathway from prolonged hypoxic vasoconstriction to vascular remodeling; fibrosis extent alone does not determine pulmonary pressure.

✶

Histopathology

1

Usual interstitial pneumonia pattern

Patchy interstitial fibrosis with temporal and spatial heterogeneity, fibroblast foci and honeycomb remodeling, most marked subpleurally and paraseptally. UIP must be interpreted with clinical and radiologic findings because it is not specific to IPF.

Show evidence (2 references)

PMID:21471066 SUPPORT Other

"The histopathologic hallmark and chief diagnostic criterion is a heterogeneous appearance at low magnification in which areas of fibrosis with scarring and honeycomb change alternate with areas of less affected or normal parenchyma"

The statement describes the heterogeneous UIP pattern.

PMID:21471066 SUPPORT Other

"The fibrotic zones are composed mainly of dense collagen, although scattered convex subepithelial foci of proliferating fibroblasts and myofibroblasts (so-called fibroblast foci) are a consistent finding."

Fibroblast foci connect the morphology to matrix-producing mesenchymal cells.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

9

Cardiovascular 1

Pulmonary hypertension Pulmonary arterial hypertension HP:0002092

The HPO term denotes elevated pulmonary arterial pressure here; this is group 3 pulmonary hypertension associated with lung disease, not a claim of group 1 PAH.

Show evidence (1 reference)

PMID:31423872 SUPPORT Other

"Although many patients with IPF‐PH have only mild PH, some have severe PH, and their prognosis remains poor."

The review documents pulmonary hypertension complicating IPF.

Limbs 1

Clubbing of fingers HP:0100759

Clinical association is supported. No directed mechanism edge is imposed because the reviewed sources do not identify its specific causal mediation.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing"

The diagnostic statement identifies these core clinical findings.

Respiratory 6

Dyspnea HP:0002094

Show evidence (1 reference)

PMID:32274173 SUPPORT Human Clinical

"Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea and limited exercise capacity."

This systematic review explicitly identifies dyspnea as a major symptomatic burden in IPF.

Respiratory failure HP:0002878

Show evidence (1 reference)

PMID:32549377 SUPPORT Other

"The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory failure and death."

This review directly links progressive architectural distortion in IPF to respiratory failure.

Cough HP:0012735

Clinical association is supported. No directed mechanism edge is imposed because the reviewed sources do not identify its specific causal mediation.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing"

The diagnostic statement identifies these core clinical findings.

Inspiratory crackles HP:0031996

Clinical association is supported. No directed mechanism edge is imposed because the reviewed sources do not identify its specific causal mediation.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing"

The diagnostic statement identifies these core clinical findings.

Hypoxemia HP:0012418

Show evidence (2 references)

PMID:21471066 SUPPORT Other

"The recommendation for long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia is strong"

The guideline recognizes clinically significant hypoxemia and its treatment.

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/ SUPPORT Other

"Hypoxemia with exertion is usually one of the earliest signs. With disease progression, hypoxemia occurs at rest."

GeneReviews describes pulmonary-fibrosis physiology; the broader inherited-PF context is applicable to the fibrotic clinical manifestation, not evidence of an IPF-specific etiology.

Restrictive ventilatory defect HP:0002091

Show evidence (3 references)

PMID:32549377 SUPPORT Other

"The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory failure and death."

This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.

PMID:24836310 SUPPORT Human Clinical

"The primary end point was the annual rate of decline in forced vital capacity (FVC)."

The pivotal IPF nintedanib trials used annual FVC decline as the primary physiologic endpoint.

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/ SUPPORT Other

"Degradation of pulmonary function occurs over time, with progressive decline of forced vital capacity and diffusion capacity."

The chapter supports longitudinal restrictive and gas-transfer impairment across fibrotic lung disease.

Constitutional 1

Exercise intolerance HP:0003546

Show evidence (1 reference)

PMID:32274173 SUPPORT Human Clinical

"Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea and limited exercise capacity."

This systematic review explicitly identifies limited exercise capacity as a core functional limitation in IPF.

🧬

Genetic Associations

8

MUC5B (Associated)

Gene: MUC5B hgnc:7516 relationship_type: RISK_FACTOR

Show evidence (2 references)

PMID:21506741 SUPPORT Human Clinical

"A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis."

This human case-control study identifies the MUC5B promoter variant rs35705950 as a major inherited susceptibility factor for IPF.

PMID:33965873 SUPPORT Other

"Key among these were the up-regulation of TGFBI, MMP7, TNF, ADAM12, activation of immune co-stimulatory markers, toll-like receptors, and increased expression of the IPF-related gene MUC5B in both minimal and established fibrotic regions of the lungs."

This review specifically identifies increased MUC5B expression as part of the molecular program present in fibrotic IPF lung tissue.

TERT (Associated)

Gene: TERT hgnc:11730 gene page relationship_type: CAUSATIVE

Autosomal dominant predisposition

Show evidence (2 references)

PMID:35078193 SUPPORT Human Clinical

"monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)"

Greek national cohort identifies TERT as the most frequently mutated telomere-related gene in heritable IPF, establishing its role as a major genetic determinant of familial pulmonary fibrosis.

PMID:33808277 SUPPORT Other

"More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis."

Review confirms that TERT and other telomere gene mutations confer worse prognosis in IPF, consistent with the mechanistic model of AT2 telomere dysfunction accelerating senescence.

TERC (Associated)

Gene: TERC hgnc:11727 gene page relationship_type: CAUSATIVE

Autosomal dominant predisposition

Show evidence (2 references)

PMID:35078193 SUPPORT Human Clinical

"monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)"

Greek national cohort identifies TERC as the second most frequently mutated telomere-related gene in heritable IPF.

PMID:33808277 SUPPORT Other

"A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs."

Review confirms TERC mutations as a cause of familial and sporadic fibrotic ILD, consistent with the AT2 telomere shortening to senescence mechanistic model.

RTEL1 (Associated)

Gene: RTEL1 hgnc:15888 gene page relationship_type: CAUSATIVE

Autosomal dominant predisposition

Show evidence (1 reference)

PMID:35078193 SUPPORT Human Clinical

"monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2)"

Greek national cohort identifies RTEL1 as a telomere-related gene mutated in heritable IPF, extending the genetic architecture beyond TERT/TERC to include DNA helicase function.

PARN

Gene: PARN hgnc:8609 gene page relationship_type: CAUSATIVE

Autosomal dominant predisposition

Show evidence (2 references)

PMID:25848748 SUPPORT Human Clinical

"PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members."

Human pedigrees link rare variants to telomere dysfunction and familial pulmonary fibrosis.

PMID:28099038 SUPPORT Human Clinical

"A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF."

Rare-variant enrichment extends the association beyond recognized familial disease.

SFTPC

Gene: SFTPC hgnc:10802 relationship_type: CAUSATIVE

Autosomal dominant inheritance with variable expression

Show evidence (2 references)

PMID:11991887 SUPPORT Human Clinical

"We show that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred"

Segregation of a heterozygous L188Q variant with familial fibrosis supports a pathogenic SFTPC relationship in a defined kindred; affected adults had UIP and affected children had cellular NSIP. This does not make SFTPC a common cause of sporadic IPF.

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf SUPPORT Other

"Pathogenic variants in the surfactant metabolism genes (SFTPA1, SFTPA2, SFTPC) are typically missense variants that lead to increased endoplasmic reticulum stress."

GeneReviews identifies pathogenic SFTPC variants as a cause of surfactant-related fibrosis predisposition; the precise mechanism depends on the variant.

SFTPA2

Gene: SFTPA2 hgnc:10799 relationship_type: CAUSATIVE

Autosomal dominant predisposition

Show evidence (2 references)

PMID:19100526 SUPPORT Human Clinical

"These data are consistent with SFTPA2 germline mutations that interfere with protein trafficking and cause familial IPF and lung cancer."

Rare pathogenic variants cause familial fibrosis with lung adenocarcinoma susceptibility; this is a specific genetic subset, not a universal IPF mechanism.

PMID:40491472 SUPPORT Human Clinical

"Specifically, heterozygous germline pathogenic or likely pathogenic variants (PGVs) in SFTPA1 and SFTPA2, which encode surfactant proteins SP-A1 and SP-A2, can result in a range of outcomes from asymptomatic cases to severe lung fibrosis and adenocarcinoma, with high mortality risks"

The pedigree study supports age-dependent variable disease expression. Pooled gene estimates, missing exposure data and competing-risk limitations prevent treating its penetrance numbers as universal IPF risks.

SFTPA1

Gene: SFTPA1 hgnc:10798 relationship_type: CAUSATIVE

Autosomal dominant predisposition

Show evidence (2 references)

PMID:26792177 SUPPORT Human Clinical

"The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma"

A multigenerational family and secretion experiments support a rare SFTPA1-related subset; this is distinct from the common SP-A1 variant tested in the TGF-beta secretion study.

PMID:40491472 SUPPORT Human Clinical

"Specifically, heterozygous germline pathogenic or likely pathogenic variants (PGVs) in SFTPA1 and SFTPA2, which encode surfactant proteins SP-A1 and SP-A2, can result in a range of outcomes from asymptomatic cases to severe lung fibrosis and adenocarcinoma, with high mortality risks"

The pedigree study supports age-dependent variable disease expression. Pooled gene estimates, missing exposure data and competing-risk limitations prevent treating its penetrance numbers as universal IPF risks.

💊

Medical Actions

9

Pirfenidone

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: pirfenidone CHEBI:32016

Oral antifibrotic therapy that slows clinical progression and FVC decline. It is not established to reverse existing scarring. Gastrointestinal and skin adverse effects and liver monitoring affect use.

Mechanism Target:

INHIBITS Fibroblast activation and myofibroblast differentiation — Attenuates TGF-beta-stimulated fibroblast activation in culture; clinical slowing of progression is independently supported by ASCEND.

Show evidence (1 reference)

PMID:24613900 SUPPORT In Vitro

"Pirfenidone reduced fibroblast proliferation and attenuated TGF-β-induced α-smooth muscle actin (SMA) and pro-collagen (Col)-I mRNA and protein levels."

Primary human lung fibroblast experiments support an antifibrotic cellular effect; the direct molecular target and mediation of human benefit are not established.

Show evidence (1 reference)

PMID:24836312 SUPPORT Human Clinical

"Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis."

The ASCEND phase 3 trial shows pirfenidone slows clinical progression in IPF.

Nintedanib

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: nintedanib CHEBI:85164

Antifibrotic tyrosine kinase inhibitor that slows the rate of forced vital capacity decline in IPF.

Mechanism Target:

INHIBITS Fibroblast activation and myofibroblast differentiation — Inhibits multiple receptor tyrosine kinases and fibroblast responses; slowing FVC decline does not isolate a single causal kinase pathway.

Show evidence (1 reference)

PMID:25745043 SUPPORT Other

"Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM."

The pharmacology review summarizes cellular mechanism evidence separately from randomized clinical efficacy.

Show evidence (1 reference)

PMID:24836310 SUPPORT Human Clinical

"In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression"

The INPULSIS phase 3 trials show nintedanib slows lung function decline in IPF.

Dasatinib and Quercetin (Senolytic Combination)

Action: Pharmacotherapy NCIT:C15986

Agent: dasatinib CHEBI:49375 quercetin CHEBI:16243

Platform: Small molecule

Investigational senolytic combination. An uncontrolled 14-participant study suggested physical-function changes without improved pulmonary function. A 12-participant randomized pilot demonstrated feasibility, with more nonserious adverse events on D+Q and no meaningful between-group functional difference. Neither study establishes antifibrotic efficacy or IPF-lung senescent-cell target engagement.

Mechanism Target:

INHIBITS Senescent myofibroblast persistence and apoptosis resistance — Targets senescent fibroblast survival in vitro; efficacy in patients remains investigational.

Show evidence (1 reference)

PMID:28230051 SUPPORT In Vitro

"We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic."

Senolysis and a profibrotic secretome are demonstrated in fibroblasts; human IPF-lung target engagement remains unproven.

Show evidence (3 references)

PMID:36857968 SUPPORT Human Clinical

"Frailty, pulmonary, or physical function were explored before and after intermittent D + Q; though under-powered to evaluate change, these measures do not appear to differ meaningfully between groups."

The randomized pilot supports feasibility, not clinical efficacy.

PMID:36857968 SUPPORT Human Clinical

"Sleep disturbances and anxiety were disproportionately represented in the D + Q arm (4/6 vs 0/6)."

Adverse-event imbalance prevents an unqualified tolerability claim.

PMID:30616998 SUPPORT Human Clinical

"Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged."

Source for the uncontrolled 14-participant result described above. The split outcome is the point: physical function improved while pulmonary function did not, so an open-label study with no comparator supports feasibility and a systemic functional signal, not antifibrotic efficacy or senescent-cell target engagement in the IPF lung.

Nerandomilast

Action: Pharmacotherapy NCIT:C15986

Agent: Nerandomilast NCIT:C203229

Platform: Small molecule

Oral preferential PDE4B inhibitor approved for adult IPF. The phase III FIBRONEER-IPF trial showed less FVC decline at 52 weeks, with most participants receiving background nintedanib or pirfenidone. Diarrhea was common. Longer follow-up did not establish a reduction in the composite of acute exacerbation, respiratory hospitalization or death, so survival benefit is not asserted.

Mechanism Target:

INHIBITS Fibroblast activation and myofibroblast differentiation — Preferential PDE4B inhibition suppresses myofibroblast transformation and proliferation in primary IPF fibroblast cultures.

Show evidence (1 reference)

PMID:35517783 SUPPORT In Vitro

"BI 1015550 inhibited transforming growth factor-β-stimulated myofibroblast transformation and the mRNA expression of various extracellular matrix proteins, as well as basic fibroblast growth factor plus interleukin-1β-induced cell proliferation."

Primary IPF fibroblast experiments support antiproliferative and differentiation effects; the 2023 corrigendum corrects Table 1 sample sizes without changing this conclusion.

Show evidence (2 references)

PMID:40387033 SUPPORT Human Clinical

"In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller decline in the FVC than placebo over a period of 52 weeks."

FIBRONEER-IPF randomized 1177 participants, most on background antifibrotics; the endpoint supports slowing decline rather than reversal.

PMID:41738262 SUPPORT Human Clinical

"nerandomilast had no effect on the composite endpoint of time to first acute exacerbation of IPF, hospitalization for respiratory cause, or death"

The final follow-up did not show benefit on this composite clinical endpoint.

Supplemental oxygen

Action: Oxygen Therapy NCIT:C94624

Corrects clinically significant hypoxemia without reversing fibrosis.

Mechanism Target:

MODULATES Hypoxemia — Corrects clinically significant hypoxemia without reversing fibrosis.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The recommendation for long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia is strong"

The guideline supports this intervention in the indicated clinical setting.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The recommendation for long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia is strong"

The guideline supports this intervention in the indicated clinical setting.

Pulmonary rehabilitation

Action: Pulmonary Rehabilitation NCIT:C157966

Exercise and supportive rehabilitation can improve functional capacity and symptoms.

Mechanism Target:

MODULATES Exercise intolerance — Exercise and supportive rehabilitation can improve functional capacity and symptoms.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The recommendation for pulmonary rehabilitation in patients with IPF is weak"

The guideline supports this intervention in the indicated clinical setting.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The recommendation for pulmonary rehabilitation in patients with IPF is weak"

The guideline supports this intervention in the indicated clinical setting.

Lung transplantation

Action: Lung Transplantation NCIT:C15274

Consider transplantation for eligible patients with progressive disease. Telomere-related marrow, immune and liver complications influence assessment and immunosuppression.

Mechanism Target:

MODULATES Architectural distortion and gas-exchange failure — Consider transplantation for eligible patients with progressive disease. Telomere-related marrow, immune and liver complications influence assessment and immunosuppression.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The recommendation for lung transplantation in appropriate patients with IPF is strong (⊕○○○)."

The guideline supports this intervention in the indicated clinical setting.

Show evidence (2 references)

PMID:21471066 SUPPORT Other

"The recommendation for lung transplantation in appropriate patients with IPF is strong (⊕○○○)."

The guideline supports this intervention in the indicated clinical setting.

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/ SUPPORT Other

"Adjustment of immunosuppressive medication may be required to avoid drug toxicities in those w/hematologic abnormalities."

Management guidance identifies a telomere-related transplant toxicity consideration rather than a blanket contraindication.

Avoid prednisone-azathioprine-N-acetylcysteine combination

This chronic three-drug regimen should not be used to treat IPF. PANTHER-IPF found excess deaths and hospitalizations without physiological or clinical benefit. This result is specific to the regimen and does not establish that immune cells have no mechanistic role or address every acute-exacerbation treatment question.

Show evidence (1 reference)

PMID:22607134 SUPPORT Human Clinical

"Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo."

The randomized PANTHER-IPF result supports avoiding this regimen.

Genetic counseling for inherited fibrosis

Offer specialist counseling when inherited pulmonary fibrosis is suspected or a pathogenic variant is identified. Discuss variable penetrance, possible anticipation and telomere inheritance, family evaluation and the distinction between variant transmission and disease prediction.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/ SUPPORT Other

"Each child of an individual with a ... associated with predisposition to pulmonary fibrosis has a 50% chance of inheriting the pathogenic variant."

The recurrence statement applies to autosomal dominant monogenic predisposition, not every sporadic IPF case; inheritance of a variant does not predict age of onset or guarantee disease.

🌍

Environmental Factors

5

Tobacco smoking

Current and former smoking are associated with IPF susceptibility in independent cohorts, with dose-response evidence. A Korean claims cohort identified 25,113 incident cases among 23,242,836 participants; smoking intensity, duration and diagnostic ascertainment affect estimates. Susceptibility is not equivalent to an identified cause in every patient.

Show evidence (2 references)

PMID:34593614 SUPPORT Human Clinical

"The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively."

Korean nationwide claims cohort supports temporality and an exposure association; diagnosis was based on codes and claims.

PMID:32660982 SUPPORT Human Clinical

"Ever smoking tobacco was associated with increased risk of IPF: OR 2.20 (95% CI 1.74 to 2.79)"

Independent Australian case-control study included 503 cases and 902 population controls.

Mechanism Target:

PREDISPOSES Repetitive alveolar epithelial injury and aberrant repair — Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.

Show evidence (2 references)

PMID:34593614 SUPPORT Human Clinical

"The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively."

Korean nationwide claims cohort supports temporality and an exposure association; diagnosis was based on codes and claims.

PMID:32660982 SUPPORT Human Clinical

"Ever smoking tobacco was associated with increased risk of IPF: OR 2.20 (95% CI 1.74 to 2.79)"

Independent Australian case-control study included 503 cases and 902 population controls.

Occupational respirable and metal dust

Occupational dust exposure is a susceptibility modifier, with inconsistent findings for particular materials. A 78-case Korean study associated metal dust with IPF, whereas an Australian 503-case study supported respirable dust overall but not specific organic, mineral or metal categories. Job-exposure matrices, coexposures and diagnostic differences limit mechanistic inference.

Show evidence (3 references)

PMID:28157473 SUPPORT Human Clinical

"After adjustment for environmental and military exposures and smoking history, the OR for metal dust exposure was 4.97 (95%CI 1.36-18.17) in multiple logistic regression analysis."

Korean matched case-control study included 78 cases and 78 controls; the interval is wide.

PMID:32660982 REFUTE Human Clinical

"However occupational exposures to other specific organic, mineral or metal dusts were not associated with IPF."

The larger Australian study did not replicate associations with these specific dust categories.

PMID:32660982 SUPPORT Human Clinical

"respirable dust (OR 1.38; 1.04 to 1.82) and asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF."

Respirable-dust association was observed even though specific metal-dust categories were null.

Mechanism Target:

PREDISPOSES Repetitive alveolar epithelial injury and aberrant repair — Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.

Show evidence (3 references)

PMID:28157473 SUPPORT Human Clinical

"After adjustment for environmental and military exposures and smoking history, the OR for metal dust exposure was 4.97 (95%CI 1.36-18.17) in multiple logistic regression analysis."

Korean matched case-control study included 78 cases and 78 controls; the interval is wide.

PMID:32660982 REFUTE Human Clinical

"However occupational exposures to other specific organic, mineral or metal dusts were not associated with IPF."

The larger Australian study did not replicate associations with these specific dust categories.

PMID:32660982 SUPPORT Human Clinical

"respirable dust (OR 1.38; 1.04 to 1.82) and asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF."

Respirable-dust association was observed even though specific metal-dust categories were null.

Occupational wood dust

Pooled observational studies associate wood-dust exposure with IPF, but smoking-adjusted estimates in an earlier meta-analysis included the null. Hardwood, softwood and job-related coexposures are not interchangeable. This is an uncertain susceptibility association rather than a sufficient cause.

Show evidence (2 references)

PMID:38096107 SUPPORT Human Clinical

"ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust."

Meta-analysis reports pooled associations; attributable fractions rely on causal assumptions and are not demonstrated prevention effects.

PMID:36253946 REFUTE Human Clinical

"Smoking adjustments: general dust (1.45 (1.04-2.03)/organic dust (2.5 (1.49-4.22)/metals (1.87 (1.16-3)/wood dust OR: 1.16 (0.86-1.61)/pesticide exposure 2.4 (0.84-6.9) were calculated."

Smoking-adjusted analysis in an earlier meta-analysis was compatible with no wood-dust association, limiting certainty.

Mechanism Target:

PREDISPOSES Repetitive alveolar epithelial injury and aberrant repair — Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.

Show evidence (2 references)

PMID:38096107 SUPPORT Human Clinical

"ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust."

Meta-analysis reports pooled associations; attributable fractions rely on causal assumptions and are not demonstrated prevention effects.

PMID:36253946 REFUTE Human Clinical

"Smoking adjustments: general dust (1.45 (1.04-2.03)/organic dust (2.5 (1.49-4.22)/metals (1.87 (1.16-3)/wood dust OR: 1.16 (0.86-1.61)/pesticide exposure 2.4 (0.84-6.9) were calculated."

Smoking-adjusted analysis in an earlier meta-analysis was compatible with no wood-dust association, limiting certainty.

Occupational asbestos exposure

An Australian IPF case-control study reported an asbestos-exposure association. Exposure history should trigger evaluation for asbestosis; disease attributable to asbestos is classified separately from IPF. Residual diagnostic misclassification and unmeasured cumulative exposure can contribute to the epidemiologic signal.

Show evidence (2 references)

PMID:32660982 SUPPORT Human Clinical

"asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF."

Reported association concerns patients classified as IPF; it does not erase the separate diagnosis of asbestosis.

PMID:21471066 SUPPORT Other

"Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity)."

Clinically established exposure-caused ILD must be excluded before assigning IPF.

Mechanism Target:

PREDISPOSES Repetitive alveolar epithelial injury and aberrant repair — Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.

Show evidence (2 references)

PMID:32660982 SUPPORT Human Clinical

"asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF."

Reported association concerns patients classified as IPF; it does not erase the separate diagnosis of asbestosis.

PMID:21471066 SUPPORT Other

"Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity)."

Clinically established exposure-caused ILD must be excluded before assigning IPF.

Occupational agricultural dust

Meta-analysis associates agricultural-dust exposure with IPF susceptibility, but jobs can combine organic antigens, mineral dust, pesticides and other agents. Established fibrotic hypersensitivity pneumonitis and pneumoconioses must be excluded; these associations do not justify reclassifying those diseases as IPF.

Show evidence (2 references)

PMID:38096107 SUPPORT Human Clinical

"ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust."

Pooled occupational associations include agricultural dust, with heterogeneity in exposure assessment and disease definition.

PMID:21471066 SUPPORT Other

"The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis)."

Antigen-mediated hypersensitivity pneumonitis is a distinct cause of fibrosis, even with a UIP pattern.

Mechanism Target:

PREDISPOSES Repetitive alveolar epithelial injury and aberrant repair — Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.

Show evidence (2 references)

PMID:38096107 SUPPORT Human Clinical

"ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust."

Pooled occupational associations include agricultural dust, with heterogeneity in exposure assessment and disease definition.

PMID:21471066 SUPPORT Other

"The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis)."

Antigen-mediated hypersensitivity pneumonitis is a distinct cause of fibrosis, even with a UIP pattern.

🔬

Biochemical Markers

4

Forced Vital Capacity (Often decreased with restrictive disease; treatment benefit is commonly a slower decline rather than restoration to normal.)

Context: Pulmonary function test readout used to measure restrictive ventilatory impairment and treatment response in pulmonary fibrosis.

Pathograph Readouts

Pharmacodynamic Marker Of Architectural distortion and gas-exchange failure Negative Regulatory Surrogate

Higher or less-declining FVC indicates less restrictive physiologic impairment from fibrotic architectural distortion; treatment-induced slowing of FVC decline reports pharmacodynamic slowing of disease progression.

FDA-SE-adult-noncancer-098 FDA

Forced vital capacity (FVC)

Traditional Validated Surrogate Endpoint

Patients with pulmonary fibrosis

Show evidence (1 reference)

PMID:24836310 SUPPORT Human Clinical

"In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression;"

The INPULSIS trials link treatment-induced slowing of FVC decline to slowed IPF disease progression.

Show evidence (1 reference)

PMID:24836310 SUPPORT Human Clinical

"The primary end point was the annual rate of decline in forced vital capacity (FVC)."

The pivotal IPF nintedanib trials used annual FVC decline as the primary physiologic endpoint.

Circulating GDF15 (Increased)

Context: Candidate marker of epithelial stress and disease severity; not an established treatment-selection test.

Pathograph Readouts

Correlates With Architectural distortion and gas-exchange failure Positive Prognostic

Circulating GDF15 associates with severity and survival, while epithelial stress is a proposed biological source. Association does not establish causal mediation.

Show evidence (1 reference)

PMID:31432710 SUPPORT Human Clinical

"circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts."

Human cohorts support a stress-associated prognostic biomarker; this does not prove a profibrotic causal action or IPF-specific senescence burden assay.

Show evidence (1 reference)

PMID:31432710 SUPPORT Human Clinical

"circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts."

Human cohorts support a stress-associated prognostic biomarker; this does not prove a profibrotic causal action or IPF-specific senescence burden assay.

Serum KL-6 (INCREASED)

Context: Regenerating type II pneumocytes produce the MUC1-associated KL-6 antigen. Elevated serum levels can correlate with prognosis but are nonspecific; they neither establish IPF alone nor prove a validated surrogate for treatment benefit.

Show evidence (2 references)

PMID:21471066 SUPPORT Other

"Serum levels of KL-6 have been shown to be elevated in patients with IPF, and these levels may correlate with increased risk of subsequent mortality"

The guideline summarizes observational serum associations, not a disease-specific diagnostic cutoff or a validated therapeutic surrogate.

PMID:30168753 SUPPORT Other

"Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs."

The diagnostic guideline prevents using a nonspecific serum biomarker alone to distinguish IPF from other interstitial lung diseases.

MMP-7 in plasma and bronchoalveolar lavage (INCREASED)

Context: MMP-7 abundance is associated with IPF and may correlate with disease severity. Circulating or lavage measurements do not directly identify the cellular source, demonstrate a required causal protease mechanism or establish response-surrogate validity.

Show evidence (2 references)

PMID:21471066 SUPPORT Other

"Studies of plasma and BAL matrix metalloproteinase (MMP) levels suggest that MMP1 and MMP7 are increased in patients with IPF, and MMP7 levels may correlate with disease severity"

The guideline supports the biochemical association while preserving uncertainty about clinical use and mechanism.

PMID:30168753 SUPPORT Other

"Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs."

The diagnostic guideline prevents using a nonspecific serum biomarker alone to distinguish IPF from other interstitial lung diseases.

🔬

Diagnosis

5

Lung biopsy for histopathologic pattern

Tissue sampling is considered when clinical and imaging assessment cannot establish a sufficiently confident diagnosis and procedural risk is acceptable. Transbronchial cryobiopsy is a conditional alternative to surgical biopsy in centers with appropriate expertise; biopsy is not mandatory for every patient without definite HRCT honeycombing.

biopsy of lung NCIT:C51748

Results: Histopathologic pattern used to establish or exclude usual interstitial pneumonia.

Show evidence (1 reference)

PMID:35486072 SUPPORT Other

"A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise."

The ATS/ERS/JRS/ALAT guideline conditionally recommends transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy where expertise exists.

High-resolution chest CT

Evaluate subpleural and basal reticulation, traction bronchiectasis and honeycombing, together with features suggesting an alternative diagnosis. Integrate the imaging pattern with clinical context.

High Resolution Computed Tomography NCIT:C20644

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"UIP is characterized on HRCT by the presence of reticular opacities, often associated with traction bronchiectasis"

The guideline describes a key radiologic UIP pattern.

Multidisciplinary diagnosis and exclusion of other ILD causes

Integrate symptoms, exposure and medication history, connective-tissue-disease evaluation, HRCT and pathology when available. A UIP pattern alone is not sufficient to identify an idiopathic cause.

Show evidence (2 references)

PMID:21471066 SUPPORT Other

"Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity)."

Alternative etiologies must be excluded before assigning IPF.

PMID:21471066 SUPPORT Other

"Thus, the accuracy of diagnosis of IPF increases with clinical, radiologic, and histopathologic correlation and can be accomplished with a multidisciplinary discussion among experienced clinical experts in the field of ILDs"

Multidisciplinary integration supports diagnostic accuracy.

Pulmonary function and oxygenation assessment

Assess FVC, diffusion capacity and oxygenation at rest and exertion to characterize impairment and follow progression. These measurements do not identify the etiology of fibrosis by themselves. FVC and DLCO, each expressed as a percentage of predicted, are the two physiologic variables of the GAP index, the staging system that assigns IPF to stages I to III by predicted mortality, and a baseline DLCO near 40 percent predicted is the threshold the 2011 ATS/ERS/JRS/ALAT statement associates with increased mortality risk.

Pulmonary Function Test NCIT:C38081

FVC percent predicted LOINC:19872-1 DLCO percent predicted LOINC:98130-8

Reference Ranges

Diffusion capacity.carbon monoxide/Predicted (ATS/ERS/JRS/ALAT 2011 statement, baseline measurement in IPF)

Below approximately 40 percent predicted (< 40.0 %) At or above approximately 40 percent predicted (≥ 40.0 %)

Below approximately 40 percent predicted: Baseline DLCO below the statement's approximate threshold; associated with an increased risk of mortality in IPF.

At or above approximately 40 percent predicted: Above the mortality-risk threshold. Still flagged LOW because DLCO in IPF is typically reduced; this band carries no claim that the value is within a population reference interval, which this row deliberately does not record.

The statement words the threshold as "approximately 40 percent predicted", so the band boundary is the statement's approximate figure, not a sharp cut-off it defines; it also specifies the measurement as single-breath and hemoglobin-corrected, while the code bound is the method-less percent-predicted DLCO. The same statement says baseline FVC is of unclear predictive value and that declines in FVC of 5-10 percent over 6 or 12 months may predict mortality; a change-over-time criterion is not a level band and is not recorded here.

Show evidence (2 references)

PMID:21471066 SUPPORT REVIEW SYNTHESIS Other

"Diffusing capacity for carbon monoxide (DlCO, single breath, hemoglobin corrected) is more reliably predictive of survival at baseline, and a threshold of approximately 40 percent predicted has been associated with an increased risk of mortality"

States the baseline DLCO threshold reproduced as the band boundary below, and its approximate character.

PMID:21471066 SUPPORT REVIEW SYNTHESIS Other

"Baseline FVC is of unclear predictive value"

Why no baseline FVC band is recorded on this row from the same statement.

Identity is bound at the method-less percent-predicted codes, LOINC:19872-1 for FVC and LOINC:98130-8 for DLCO, because the GAP index and the pivotal trials express both as a fraction of predicted; the absolute-volume FVC code (LOINC:19870-5) sits on the Forced Vital Capacity biochemical marker. No GAP bands are recorded: the GAP derivation paper (PMID:22586007) is cached as abstract only, and its abstract names FVC and DLCO as the two physiology variables and reports stage I to III mortality without stating the FVC or DLCO point thresholds. They can be added when a cached record of the paper carries them in quotable text.

Show evidence (4 references)

PMID:22586007 SUPPORT PRIMARY RESULT Human Clinical

"Four variables were included in the final model: gender (G), age (A), and 2 lung physiology variables (P) (FVC and Dlco)."

The GAP derivation names FVC and DLCO as the two physiologic variables of the IPF staging system, which is why both are bound as measurements on this row.

PMID:22586007 SUPPORT PRIMARY RESULT Human Clinical

"Three stages (stages I, II, and III) were identified based on the GAP index with 1-year mortality of 6%, 16%, and 39%, respectively."

The staging these two measurements feed; recorded as the row's staging claim, with the point thresholds left unbanded because the abstract does not state them.

PMID:24836310 SUPPORT Human Clinical

"The primary end point was the annual rate of decline in forced vital capacity (FVC)."

The pivotal IPF nintedanib trials used annual FVC decline as the primary physiologic endpoint.

+ 1 more reference

Genetic and telomere evaluation in at-risk patients

Family history, young onset, premature graying, cytopenias or liver disease can suggest inherited fibrosis or a telomere biology disorder. Consider specialist genetic evaluation and telomere testing in the appropriate context; blood telomere length is not a direct AT2 senescence measurement or a stand-alone IPF diagnosis.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/ SUPPORT Other

"Telomere length measurement should be offered to individuals with pulmonary fibrosis and extrapulmonary manifestations of a short telomere syndrome"

The chapter recommends targeted telomere assessment in patients with syndromic clues; this does not require universal testing or establish IPF solely from a short result.

📈

Progression

2

Progressive fibrotic decline

Course is heterogeneous: gradual decline, periods of relative stability and acute deterioration occur. Historical cohorts often report median survival of two to five years, which is not an individual prediction and predates some current therapies.

Show evidence (1 reference)

PMID:33965873 SUPPORT Other

"Although the survival of patients with idiopathic pulmonary fibrosis (IPF) still hovers around a median of two to five years"

The review summarizes the poor medium-term prognosis that characterizes progressive IPF.

Coexisting conditions affecting evaluation and care

Pulmonary hypertension, emphysema or combined pulmonary fibrosis and emphysema, gastroesophageal reflux, sleep apnea, obesity, coronary artery disease, pulmonary embolism and lung cancer can coexist with IPF. They require clinical consideration without being assumed to arise from one universal IPF mechanism or to explain every deterioration. The cited guideline does not supply disease-specific prevalence estimates or justify universal screening protocols. Treating symptomatic reflux has its own indications; the 2022 guideline conditionally recommends against antacid medication or antireflux surgery solely as IPF treatment.

Show evidence (3 references)

PMID:21471066 SUPPORT Other

"Patients with IPF may have sub-clinical or overt co-morbid conditions including pulmonary hypertension, gastroesophageal reflux, obstructive sleep apnea, obesity, and emphysema."

The guideline identifies coexisting conditions without asserting that IPF causes every condition or that treating them reverses fibrosis.

PMID:21471066 SUPPORT Other

"Comorbidities including pulmonary hypertension, pulmonary embolism, lung cancer, and coronary artery disease are known to occur in IPF."

The guideline adds vascular and malignant comorbidity context; no universal prevalence, screening benefit or causal arrow is inferred.

PMID:35486072 SUPPORT Other

"Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF."

The current guideline distinguishes IPF-directed treatment claims from management of symptomatic reflux on its own merits.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Idiopathic Pulmonary Fibrosis:

Connective tissue disease-associated ILD

Overlapping Features Can produce fibrotic interstitial lung disease with an overlapping UIP pattern.

Distinguishing Features

Assess systemic rheumatic manifestations and serology in the clinical context.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis)."

The source identifies major alternative causes of a UIP pattern.

Fibrotic hypersensitivity pneumonitis

Overlapping Features Can produce fibrotic interstitial lung disease with an overlapping UIP pattern.

Distinguishing Features

Assess antigen exposure, air trapping and other clinical, imaging and pathologic evidence.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis)."

The source identifies major alternative causes of a UIP pattern.

Asbestosis

Overlapping Features Can produce fibrotic interstitial lung disease with an overlapping UIP pattern.

Distinguishing Features

Assess occupational asbestos exposure and pleural or other compatible imaging findings.

Show evidence (1 reference)

PMID:21471066 SUPPORT Other

"The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis)."

The source identifies major alternative causes of a UIP pattern.

📊

Related Datasets

8

Single-cell RNA-sequencing of normal and fibrotic human lungs (collagen-producing lung cell atlas) scea:E-CURD-126

EBI Single Cell Expression Atlas harmonized re-analysis (102,932 cells) of the Tsukui et al. collagen-producing lung cell atlas, restricted to the human lung subset (normal, idiopathic pulmonary fibrosis, and scleroderma). Resolves collagen-producing mesenchymal heterogeneity and identifies CTHRC1-expressing fibroblasts that appear uniquely in fibrotic lungs and concentrate within fibroblastic foci — cell-resolution support for the activated-mesenchymal-cell and excessive-ECM steps of the fibrotic_response module to which this entry conforms.

human SINGLE CELL RNA SEQ droplet single-cell RNA-seq (10x Genomics)

fibrotic and normal lung tissue UBERON:0002048

Conditions: idiopathic pulmonary fibrosis systemic sclerosis (scleroderma) lung normal lung

PMID:32317643

Aggregator provenance: the harmonized re-analysis is hosted by the EBI Single Cell Expression Atlas (accession E-CURD-126); the underlying study is Tsukui et al., Nat Commun 2020 (PMID:32317643, DOI:10.1038/s41467-020-15647-5). The original study is a mixed murine + human atlas; only the human lung subset is cited here (evidence_source HUMAN_CLINICAL).

Show evidence (1 reference)

PMID:32317643 SUPPORT Human Clinical

"Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs."

Human scRNA-seq (the subset harmonized as SCEA E-CURD-126) shows CTHRC1-expressing fibroblasts arising specifically in fibrotic lungs, giving cell-resolution support for the pathogenic mesenchymal-cell / excessive-ECM nodes of the fibrotic_response module.

Activation of Fibroblast LRP1 by AT2-secreted MDK Affects OTUB1/SLC7A11 Ubiquitination to Inhibit Fibroblast Ferroptosis in Idiopathic Pulmonary Fibrosis. geo:GSE262882

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial fibrosing pneumonia of unknown cause, is characterized by an irreversible decrease in alveolar cells and an increase in fibroblasts. In our research, the numbers of AT2 cells and fibroblasts are abnormally regulated, but AT1 cells are significantly reduced in lung tissue sections from patients with IPF and mice. By analyzing the single-cell sequence from GEO database and experimental validation both in vivo and in vitro, it is found that the abnormally regulated AT2 cells secreting a large amount of MDK to activate the CTHRC1+ fibroblasts LRP1 receptor and inhibit the ferroptosis of fibroblasts.

human SINGLE CELL RNA SEQ n=6

PMID:42305620

Identified by GEO DataSets index search for Idiopathic Pulmonary Fibrosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Toll-Like-Receptor 5 Reduces Lung Dysbiosis and Protects Against Pulmonary Fibrosis geo:GSE314583

Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation. IPF results from maladaptive responses to lung epithelial injury, but the underlying mechanisms remain unclear. Here, we show that deficiency in the innate immune receptor, toll-like receptor 5 (TLR5), is associated with IPF in humans and with increased susceptibility to experimental fibrosis in mice, while activation of lung epithelial TLR5 through a synthetic flagellin analog protects from experimental fibrosis. Mechanistically, epithelial TLR5 activation induces antimicrobial gene expression and ameliorates dysbiosis after lung injury.

mouse n=106

PMID:42234773

Identified by GEO DataSets index search for Idiopathic Pulmonary Fibrosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

The transition from normal lung anatomy to minimal and established fibrosis in Idiopathic Pulmonary Fibrosis ega:EGAS00001004758

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Idiopathic Pulmonary Fibrosis"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Profibrotic priming of airway cell types in idiopathic pulmonary fibrosis and drug inhibition in single-cell resolution ega:EGAS00001005794

The cause and etiology of idiopathic pulmonary fibrosis, a severe chronic lung disorder with limited treatment options, is still poorly understood. Early genetic studies hinted that airway epithelial cells play an important role in the development of IPF while more recent single-cell RNA sequencing atlases from explant IPF lungs have focused on macrophages. In this study, we used air-liquid interface cultures of primary cells taken from the subsegmental bronchi of IPF patients, reflecting early-stage fibrosis, to interrogate the single-cell transcriptional landscape of the airway mucosa. We identified IPF-enriched cell-cell interaction pathways.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Idiopathic Pulmonary Fibrosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

O-GlcNAc Containing Proteins in Normal and Idiopathic Pulmonary Fibrosis Human Fibroblasts massive:MSV000093453

Isolated normal and IPF fibroblasts were homogenized in cold MilliQ water using a bullet blender. Samples were centrifuged and inhibitors were added: HALT (Thermo Fisher Scientific), Z-Pugnac (Tocris), Thiamet G (Cayman Chemicals), and benzonase (E1014, Millipore, Sigma). O-GlcNAc enzymatic labeling and protein capturing was performed as described using a Click-IT enrichment kit following the manufacturer's protocol (cat no: C33368, C33372, and C10416; Thermo Fisher Scientific).

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Idiopathic Pulmonary Fibrosis"). Retrieved 2026-08-02.

Markers of neutrophil degranulation in the lung microenvironment linked to idiopathic pulmonary fibrosis severity and survival massive:MSV000098032

Idiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying circulating prognostic markers. Using a proteomic discovery method followed by ELISA confirmation in multiple cohorts we explored novel markers of IPF survival in bronchoalveolar lavage fluid (BALF)

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Idiopathic Pulmonary Fibrosis"). Retrieved 2026-08-02.

Proteomic profiling of bronchoalveolar lavage fluid uncovers unique protein clusters linked to survival in idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features massive:MSV000094806

This study aimed to delineate molecular phenotypes of the lung microenvironment across idiopathic interestitial pneumonias, namely interstitial pneumonia with autoimmune features (IPAF)and idiopathic pulmonary fibrosis (IPF) through proteomic analysis of bronchoalveolar lavage fluid (BALF).

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Idiopathic Pulmonary Fibrosis"). Retrieved 2026-08-02.

🔬

Clinical Trials

2

NCT05321069 PHASE_III COMPLETED

FIBRONEER-IPF evaluated two nerandomilast doses versus placebo, including patients on background antifibrotics. The published primary endpoint was FVC change at 52 weeks.

Show evidence (1 reference)

clinicaltrials:NCT05321069 SUPPORT Human Clinical

"If they already take nintedanib or pirfenidone for their IPF, they can continue treatment throughout the study."

The registry documents allowed background therapy.

NCT02874989 PHASE_I COMPLETED

Senolytic D+Q pilot program comprising open-label and randomized components, with 26 actual participants in the registry. Published components involved 14 open-label and 12 randomized participants.

Show evidence (1 reference)

clinicaltrials:NCT02874989 SUPPORT Human Clinical

"The study team hypothesizes that intermittent (3 doses administered over 3 consecutive days in 3 consecutive weeks) oral administration of combination Dasatinib (100 mg/d) + Quercetin (1250 mg/d) will be safe and well tolerated in patients with IPF."

Registry text describes the hypothesis and schedule, not a demonstrated safety or efficacy result.

🧫

Experimental Models

2

Microengineered alveolar array lung-on-chip with breathing mechanics ORGAN_ON_CHIP namo:OrganOnChip

An array of geometrically defined alveolar units suspended on a thin collagen-elastin hydrogel membrane engineered to match the dimensions and mechanical fragility of the native alveolar basement membrane, with human alveolar epithelial cells and lung fibroblasts co-cultured across it and subjected to controlled cyclic deflection emulating breathing. Precision injection moulding and an SBS microwell format make it medium-throughput, which is what allows drug testing rather than single-device demonstration.

Organism

human NCBITaxon:9606

Tissue

alveolus of lung UBERON:0002299

Culture

Injection-moulded alveolar array chip with suspended collagen-elastin hydrogel membrane and cyclic actuation

Publication

PMID:41406599

Pathograph links

Fibroblast activation and myofibroblast differentiation recapitulates fidelity: moderate Cyclic stretch applied together with TGF-beta 1 amplified fibrotic signalling well beyond TGF-beta 1 alone. This makes breathing motion an explicit cofactor of fibroblast activation rather than background, which is the mechanistic claim a static culture cannot test.

Limitations: Amplification was demonstrated with exogenous TGF-beta 1 rather than with the endogenous injury signals of IPF, and the co-culture uses non-diseased alveolar epithelial cells and fibroblasts, so it models the mechanical contribution to fibrotic signalling rather than IPF-specific fibroblast biology such as the aberrant basaloid state.

Readouts

Extracellular matrix gene expression under cyclic stretch with TGF-beta 1

Direction: INCREASED

Interpretation: Collagen I, collagen III, and fibronectin induction is the activation readout, and its stretch-dependence is the finding.

Show evidence (1 reference)

PMID:41406599 SUPPORT In Vitro

"We demonstrate that cyclic stretching significantly amplifies fibrotic signaling in the presence of transforming growth factor-beta 1 (TGF-β1), evidenced by increased expression of extracellular matrix (ECM) components such as collagen I, collagen III, and fibronectin."

Reports the matrix-gene induction and its dependence on cyclic stretch.

Show evidence (1 reference)

PMID:41406599 SUPPORT In Vitro

"Human alveolar epithelial cells and lung fibroblasts are co-cultured on a membrane and subjected to cyclic biomechanical stress that mimics respiratory movements."

Establishes the epithelial-fibroblast co-culture under breathing mechanics as the model configuration relevant to this node.

Excessive extracellular matrix deposition partially recapitulates fidelity: moderate Matrix protein and PAI-1 expression rose under profibrotic stimulation and fell with nintedanib, an approved IPF antifibrotic, giving the model pharmacological validation against the standard of care for this node.

Limitations: Readouts are expression-level over days rather than accumulated cross-linked matrix, and nintedanib reversal establishes assay responsiveness rather than predictive value for novel compounds. The membrane is a defined collagen-elastin hydrogel, not fibrotic human lung matrix, so matrix-stiffness feedback is not reproduced.

Readouts

ECM protein and PAI-1 expression under nintedanib

Direction: DECREASED

Interpretation: Reduction by an approved antifibrotic confirms the readout responds in the therapeutically expected direction.

Show evidence (1 reference)

PMID:41406599 SUPPORT In Vitro

"Treatment with the anti-fibrotic drug nintedanib reduced expression of ECM proteins and plasminogen activator inhibitor-1 (PAI-1), validating the system's utility for pharmacological testing."

Directly reports the drug-responsive matrix readout.

Show evidence (1 reference)

PMID:41406599 SUPPORT In Vitro

"Treatment with the anti-fibrotic drug nintedanib reduced expression of ECM proteins and plasminogen activator inhibitor-1 (PAI-1), validating the system's utility for pharmacological testing."

Supports a drug-responsive expression surrogate for matrix deposition, without directly measuring accumulated cross-linked scar.

Immune-cell-free AT2-lineage and fibroblast organoids ORGANOID

Mouse and human lung-derived organoid co-cultures exposed to bleomycin isolate direct epithelial-fibroblast signaling. The assay tests an immune-cell-free route under defined conditions.

Cell source

Mouse and human lung-derived epithelial cells and fibroblasts

Publication

PMID:37653024

Pathograph links

AT2 cell senescence and SASP recapitulates fidelity: moderate Bleomycin-induced DNA damage activates p53 and a profibrotic secretory epithelial state.

Limitations: Organoids lack the immune, vascular and whole-organ context; experimental sufficiency does not establish in-vivo immune independence.

Readouts

p53-associated SASP and myofibroblast induction

Direction: INCREASED

Interpretation: Bleomycin-induced DNA damage activates p53 and a profibrotic secretory epithelial state.

Show evidence (1 reference)

PMID:37653024 SUPPORT In Vitro

"bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast..."

The immune-cell-free organoid experiment establishes epithelial-fibroblast sufficiency under bleomycin stimulation; accompanying mouse genetics do not imply immune independence of whole-animal disease.

Show evidence (1 reference)

PMID:37653024 SUPPORT In Vitro

"bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast..."

The immune-cell-free organoid experiment establishes epithelial-fibroblast sufficiency under bleomycin stimulation; accompanying mouse genetics do not imply immune independence of whole-animal disease.

Show evidence (1 reference)

PMID:37653024 SUPPORT In Vitro

"Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells."

The co-culture removes immune cells to isolate epithelial-mesenchymal communication.

🐁

Animal Models

3

AT2-specific TRF1 conditional deletion

Prolonged AT2 shelterin deletion produces spontaneous senescence-associated remodeling and collagen deposition, unlike the collagen-expressing-cell deletion comparator.

Species

Mus musculus

Genotype

SPC-Cre TRF1fl/fl

Publication

PMID:27699234

Pathograph links

Alveolar epithelial telomere dysfunction perturbs fidelity: moderate TRF1 loss perturbs telomere protection and eventually shortens telomeres.

Limitations: Severe engineered uncapping and mouse telomere biology differ from ordinary human age-related attrition.

Readouts

Epithelial senescence and collagen deposition

Direction: INCREASED

Interpretation: TRF1 loss perturbs telomere protection and eventually shortens telomeres.

Show evidence (1 reference)

PMID:27699234 SUPPORT Model Organism

"Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells."

Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.

Show evidence (1 reference)

PMID:27699234 SUPPORT Model Organism

"Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells."

Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.

Excessive extracellular matrix deposition recapitulates fidelity: moderate Collagen deposition increases after prolonged epithelial telomere dysfunction.

Limitations: Spontaneous experimental fibrosis does not establish the initiating lesion or immune independence of every human case.

Readouts

Lung collagen deposition

Direction: INCREASED

Interpretation: Collagen deposition increases after prolonged epithelial telomere dysfunction.

Show evidence (1 reference)

PMID:27699234 SUPPORT Model Organism

"Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells."

Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.

Show evidence (1 reference)

PMID:27699234 SUPPORT Model Organism

"Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells."

Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.

Show evidence (1 reference)

PMID:27699234 SUPPORT Model Organism

"Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells."

Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.

AT2-specific Sin3a conditional loss

Induced p53-dependent AT2 senescence produces progressive fibrosis; comparison with conditional AT2 ablation distinguishes senescence from simple cell loss.

Species

Mus musculus

Genotype

Conditional Sin3a loss in adult Sftpc-expressing AT2 cells

Publication

PMID:32991815

Pathograph links

AT2 cell senescence and SASP perturbs fidelity: moderate Conditional Sin3a loss induces p53-dependent senescence, AT2 depletion and spontaneous fibrosis.

Limitations: Engineered Sin3a loss establishes mechanistic sufficiency in mice, not a common human initiating lesion.

Readouts

AT2 senescence and progressive fibrosis

Direction: INCREASED

Interpretation: Conditional Sin3a loss induces p53-dependent senescence, AT2 depletion and spontaneous fibrosis.

Show evidence (1 reference)

PMID:32991815 SUPPORT Model Organism

"We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis."

An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin; it does not establish immune independence or the initiating lesion in all human IPF.

Show evidence (1 reference)

PMID:32991815 SUPPORT Model Organism

"We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis."

An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin; it does not establish immune independence or the initiating lesion in all human IPF.

Erratum PMID:34256008 corrects figure alignment, panel labels and the comparator mouse line to RosaDTA; it does not withdraw the spontaneous-fibrosis result.

Show evidence (1 reference)

PMID:32991815 SUPPORT Model Organism

"We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis."

An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin; it does not establish immune independence or the initiating lesion in all human IPF.

AT2-specific TERT conditional deletion with bleomycin

TERT deletion alone did not cause fibrosis over 9 months, but increased injury-associated senescence and fibrosis after bleomycin without a significant effect on measured AT2 telomere length.

Species

Mus musculus

Genotype

SPC-Tert conditional knockout

Publication

PMID:31000627

Pathograph links

AT2 cell senescence and SASP perturbs fidelity: moderate TERT deficiency heightens senescence and impairs regeneration after injury.

Limitations: This is a TERT-function perturbation with a second-hit requirement, not interchangeable evidence for telomere shortening.

Readouts

Injury-associated fibrosis and cytokine expression

Direction: INCREASED

Interpretation: TERT deficiency heightens senescence and impairs regeneration after injury.

Show evidence (1 reference)

PMID:31000627 SUPPORT Model Organism

"However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis compared with control mice, accompanied by increased pro-fibrogenic cytokine expression but without a significant effect on AECII telomere length."

TERT loss amplifies injury-associated fibrosis without measurable telomere shortening in this model.

Show evidence (1 reference)

PMID:31000627 SUPPORT Model Organism

"However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis compared with control mice, accompanied by increased pro-fibrogenic cytokine expression but without a significant effect on AECII telomere length."

TERT loss amplifies injury-associated fibrosis without measurable telomere shortening in this model.

Show evidence (1 reference)

PMID:31000627 SUPPORT Model Organism

"However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis compared with control mice, accompanied by increased pro-fibrogenic cytokine expression but without a significant effect on AECII telomere length."

TERT loss amplifies injury-associated fibrosis without measurable telomere shortening in this model.

{ }

Source YAML

click to show

name: Idiopathic Pulmonary Fibrosis
creation_date: "2026-04-11T00:00:00Z"
category: Respiratory Disease
parents:
- Respiratory Disease
- Lung Disease
disease_term:
  preferred_term: idiopathic pulmonary fibrosis
  term:
    id: MONDO:0800504
    label: idiopathic pulmonary fibrosis
gene_sets:
- gene_set: MYGENESET:WP_LUNG_FIBROSIS
  relationship: CANONICAL_PATHWAY
  note: >-
    WikiPathways lung fibrosis pathway.
description: >-
  A chronic progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older
  adults and associated with the usual interstitial pneumonia (UIP) radiologic and histologic pattern.
  Alveolar epithelial dysfunction, impaired regeneration, fibroblast activation and persistent matrix
  remodeling reduce lung compliance and gas exchange. IPF is diagnosed after exclusion of alternative
  causes of interstitial lung disease; UIP is not specific to IPF. Familial pulmonary fibrosis and telomere
  biology disorders overlap with IPF but also produce other interstitial lung disease diagnoses.
synonyms:
- IPF
- cryptogenic fibrosing alveolitis
- idiopathic fibrosing alveolitis
progression:
- phase: Progressive fibrotic decline
  notes: >-
    Course is heterogeneous: gradual decline, periods of relative stability and acute deterioration occur.
    Historical cohorts often report median survival of two to five years, which is not an individual prediction
    and predates some current therapies.
  evidence:
  - reference: PMID:33965873
    reference_title: "Molecular pathways in idiopathic pulmonary fibrosis pathogenesis: Transcending barriers to optimally targeted pharmacotherapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although the survival of patients with idiopathic pulmonary fibrosis (IPF) still hovers around a
      median of two to five years
    explanation: The review summarizes the poor medium-term prognosis that characterizes progressive IPF.
- phase: Coexisting conditions affecting evaluation and care
  notes: Pulmonary hypertension, emphysema or combined pulmonary fibrosis and emphysema, gastroesophageal reflux, sleep apnea, obesity, coronary artery disease, pulmonary embolism and lung cancer can coexist with IPF. They require clinical consideration without being assumed to arise from one universal IPF mechanism or to explain every deterioration. The cited guideline does not supply disease-specific prevalence estimates or justify universal screening protocols. Treating symptomatic reflux has its own indications; the 2022 guideline conditionally recommends against antacid medication or antireflux surgery solely as IPF treatment.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Patients with IPF may have sub-clinical or overt co-morbid conditions including pulmonary hypertension, gastroesophageal reflux, obstructive sleep apnea, obesity, and emphysema.
    explanation: The guideline identifies coexisting conditions without asserting that IPF causes every condition or that treating them reverses fibrosis.
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Comorbidities including pulmonary hypertension, pulmonary embolism, lung cancer, and coronary artery disease are known to occur in IPF.
    explanation: The guideline adds vascular and malignant comorbidity context; no universal prevalence, screening benefit or causal arrow is inferred.
  - reference: PMID:35486072
    reference_title: 'Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF.
    explanation: The current guideline distinguishes IPF-directed treatment claims from management of symptomatic reflux on its own merits.
pathophysiology:
- name: Repetitive alveolar epithelial injury and aberrant repair
  description: >-
    Recurrent injury to alveolar epithelial cells, particularly type II pneumocytes, initiates a dysregulated
    wound-healing response that fails to restore normal alveolar architecture and instead drives fibrotic
    remodeling.
  conforms_to: "fibrotic_response#Tissue Injury"
  role: trigger
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DYSREGULATED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:35563849
    reference_title: "Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response,
      during which fibroblasts differentiate into myofibroblasts.
    explanation: This review directly supports repetitive epithelial injury as the initiating trigger for maladaptive wound healing in IPF.
  - reference: PMID:33201251
    reference_title: "Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and
      epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling.
    explanation: This review links epithelial apoptosis and senescence to the abnormal remodeling response after lung injury in IPF.
  downstream:
  - target: AT2 cell senescence and SASP
    description: >-
      Bleomycin-induced DNA damage activates p53 and a senescent transitional epithelial state.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37653024
      reference_title: "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1
        transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related
        factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation.
        Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular
        system in non-inflammatory lung fibrogenesis.
      explanation: >-
        The immune-cell-free organoid experiment establishes epithelial-fibroblast sufficiency under bleomycin
        stimulation; accompanying mouse genetics do not imply immune independence of whole-animal disease.
  - target: Profibrotic macrophage recruitment and amplification
    description: >-
      Injured epithelium produces CCR2 ligands that promote exudate macrophage recruitment in a mouse
      injury model.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31922885
      reference_title: Diverse Injury Pathways Induce Alveolar Epithelial Cell CCL2/12, Which Promotes Lung Fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In contrast, mice with lung epithelial cell-specific deletion of CCL12 were protected from bleomycin-induced
        fibrosis and had expression of CCL2 and CCL7 similar to that of control mice treated with bleomycin.
        Deletion of CCL12 within AECs led to decreased recruitment of exudate macrophages.
      explanation: >-
        Epithelial CCL12 contributes to macrophage recruitment in this mouse injury model; global CCL12
        deletion was not protective and this is not universal immune necessity.
  - target: Self-DNA sensing through epithelial cGAS
    description: >-
      DNA-damaging epithelial stress increases mitochondrial DNA in cytosolic and extracellular compartments
      in primary cultures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34524912
      reference_title: 'A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Higher levels of mtDNA were detected in the cytosol and culture supernatants of primary IPF- and
        etoposide-treated Ctrl-AECs when compared with Ctrl-AECs at baseline.
      explanation: >-
        The cultured-cell compartment measurements support self-DNA exposure after damage, not universal
        cGAS/STING dependence.
- name: AT2 cell senescence and SASP
  description: >-
    AT2-lineage cells can enter a stress-associated senescent state with reduced regenerative capacity
    and a secretory program that activates fibroblasts. DNA damage, telomere dysfunction, chronic Wnt
    signaling and metabolic stress are candidate upstream routes. Bleomycin-treated epithelial-fibroblast
    organoids show autocrine TGF-beta feedback and paracrine myofibroblast induction without immune cells.
    In vivo models establish senescence as a possible proximal driver, while the contribution of immune
    recruitment varies by model and cannot be declared universally necessary or dispensable.
  conforms_to: "cellular_senescence#Senescent Cell Accumulation"
  role: amplifier
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  - preferred_term: TGF-beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:37653024
    reference_title: "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1
      transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related
      factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation.
      Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular
      system in non-inflammatory lung fibrogenesis.
    explanation: >-
      The immune-cell-free organoid experiment establishes epithelial-fibroblast sufficiency under bleomycin
      stimulation; accompanying mouse genetics do not imply immune independence of whole-animal disease.
  - reference: PMID:34813355
    reference_title: "Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors
      (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic
      dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair.
    explanation: >-
      Annual Review of Pathology 2022 review places AT2 senescence as a consequence of recurrent injury
      that bridges injury to downstream fibrotic mechanisms.
  - reference: PMID:32991815
    reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent
      cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis.
    explanation: >-
      An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin;
      it does not establish immune independence or the initiating lesion in all human IPF.
  downstream:
  - target: Persistent epithelial and mesenchymal TGF-beta signaling
    description: >-
      Senescent profibrotic AT2-lineage cells produce TGF-beta in the organoid system.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37653024
      reference_title: Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast
        differentiation.
      explanation: >-
        Within the tested organoid system, epithelial TGF-beta mediates fibroblast differentiation; the
        exclusivity is assay-specific.
  - target: AT2 progenitor exhaustion and impaired alveolar regeneration
    description: >-
      Senescence impairs epithelial regeneration and produces AT2 depletion in the Sin3a perturbation
      model.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32991815
      reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent
        cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis.
      explanation: >-
        An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin;
        it does not establish immune independence or the initiating lesion in all human IPF.
- name: Alveolar epithelial telomere dysfunction
  conforms_to: "telomere_attrition#Telomere-Initiated DNA Damage and Replicative Senescence"
  description: >-
    Pathogenic telomere-maintenance variants and age-related shortening can produce dysfunctional telomeres
    and persistent DNA-damage signaling in alveolar epithelial cells. The human genetic evidence supports
    susceptibility, with incomplete penetrance. Experimental shelterin/TRF1 uncapping can induce spontaneous
    lung fibrosis, whereas AT2-specific TERT loss increases bleomycin susceptibility without measurable
    telomere shortening in one model. These perturbations must not be treated as interchangeable demonstrations
    of physiological telomere attrition.
  role: trigger
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: telomere maintenance
    term:
      id: GO:0000723
      label: telomere maintenance
    modifier: DECREASED
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:17392301
    reference_title: Telomerase mutations in families with idiopathic pulmonary fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short
      telomeres.
    explanation: >-
      The familial cohort demonstrates pathogenic telomerase variants and short telomeres. Unaffected
      carriers also had short telomeres, showing incomplete disease penetrance.
  - reference: PMID:27699234
    reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing
      cells, leads to age-dependent lung remodeling and fibrosis.
    explanation: >-
      Conditional TRF1 deletion causes spontaneous fibrosis after prolonged epithelial telomere dysfunction;
      this severe uncapping model is distinct from ordinary age-related shortening.
  - reference: PMID:25848748
    reference_title: Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic
      inheritance of short telomeres in family members.
    explanation: >-
      Human pedigrees link rare variants to telomere dysfunction and familial pulmonary fibrosis.
  - reference: PMID:30067250
    reference_title: Clinical implications of telomere dysfunction in lung fibrosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Reduced telomere length may be identified in a quarter of patients with sporadic idiopathic pulmonary
      fibrosis (IPF) and half of those cases with family aggregation
    explanation: >-
      A clinical review quantifying how often measurably short telomeres are detected, with the expected
      enrichment in familial disease. This supports treating this node as a susceptibility route present
      in a subset rather than in all patients. The figure describes detectable shortening in the assayed
      compartment, usually leukocytes, and is not a measurement of the fraction of IPF mediated by alveolar
      epithelial senescence.
  downstream:
  - target: AT2 cell senescence and SASP
    description: >-
      Telomere dysfunction activates a persistent DNA-damage response and senescence in AT2 cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27699234
      reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing
        cells, leads to age-dependent lung remodeling and fibrosis.
      explanation: >-
        Conditional TRF1 deletion causes spontaneous fibrosis after prolonged epithelial telomere dysfunction;
        this severe uncapping model is distinct from ordinary age-related shortening.
    hypothesis_groups:
    - senescence_first_model
  - target: AT2 progenitor exhaustion and impaired alveolar regeneration
    description: >-
      Dysfunctional telomeres impair alveolar epithelial renewal; this contribution depends on the genetic
      and injury context.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27699234
      reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing
        cells, leads to age-dependent lung remodeling and fibrosis.
      explanation: >-
        Conditional TRF1 deletion causes spontaneous fibrosis after prolonged epithelial telomere dysfunction;
        this severe uncapping model is distinct from ordinary age-related shortening.
    hypothesis_groups:
    - senescence_first_model
  genes:
  - preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  - preferred_term: TERC
    term:
      id: hgnc:11727
      label: TERC
  - preferred_term: RTEL1
    term:
      id: hgnc:15888
      label: RTEL1
  - preferred_term: PARN
    term:
      id: hgnc:8609
      label: PARN
- name: AT2 progenitor exhaustion and impaired alveolar regeneration
  conforms_to: "stem_cell_exhaustion#Decline in Stem Cell Self-Renewal and Function"
  description: >-
    AT2 cells normally regenerate the alveolar epithelium. Senescence and telomere dysfunction impair
    renewal and can deplete functional progenitors. Cell loss and a persistent senescent secretory state
    are distinct mechanisms: the Sin3a model distinguishes progressive senescence-associated fibrosis
    from transient remodeling after AT2 ablation.
  role: effector
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: stem cell population maintenance
    term:
      id: GO:0019827
      label: stem cell population maintenance
    modifier: DECREASED
  - preferred_term: tissue regeneration
    term:
      id: GO:0042246
      label: tissue regeneration
    modifier: DECREASED
  evidence:
  - reference: PMID:18753630
    reference_title: "Short telomeres are a risk factor for idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short telomeres limit tissue renewal capacity in the lung and germ-line mutations in telomerase
      components, hTERT and hTR, underlie inheritance in a subset of families with IPF.
    explanation: >-
      Establishes that short telomeres limit lung tissue-renewal capacity, supporting exhaustion of the
      alveolar type II progenitor pool. Evidence source is HUMAN_CLINICAL (patient telomere-length study).
  - reference: PMID:32991815
    reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show
      that either genetic or pharmacologic interventions targeting p53 activation or senescence block
      fibrogenesis.
    explanation: >-
      Senescence-associated dysfunction cannot be reduced to simple progenitor depletion.
  downstream:
  - target: Architectural distortion and gas-exchange failure
    description: >-
      Persistent failure of epithelial restoration contributes to progressive remodeling; simple cell
      ablation alone need not cause progressive fibrosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32991815
      reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show
        that either genetic or pharmacologic interventions targeting p53 activation or senescence block
        fibrogenesis.
      explanation: >-
        Senescence-associated dysfunction cannot be reduced to simple progenitor depletion.
- name: Aberrant basaloid cell emergence
  description: >-
    KRT5-negative/KRT17-positive aberrant basaloid epithelial cells coexpress basal, mesenchymal and senescence-related
    markers and occur near myofibroblast foci in fibrotic human lungs. Their transcriptome is a disease-associated
    state rather than proof of epithelial conversion into fibroblasts. Human AT2 cultures can undergo
    a basal transition under defined signaling conditions, but the origin and causal contribution of every
    basaloid cell population in human IPF remain unresolved.
  role: consequence
  cell_types:
  - preferred_term: aberrant basaloid epithelial cell
    term:
      id: CL:0000646
      label: basal cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
    modifier: INCREASED
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  evidence:
  - reference: PMID:33859634
    reference_title: "Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Within both the IPF and SSc-ILD samples we identified a small population of the recently described
      aberrant basaloid cells (or KRT5-/KRT17+ cells), with no cells sharing this distinct transcriptome
      amongst the control samples
    explanation: >-
      Human single-cell data identify this population in both IPF and SSc-ILD, so it is not specific to
      IPF and does not establish senescence-to-basaloid lineage causality.
  - reference: PMID:34813355
    reference_title: "Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell,
      which may disrupt normal epithelial repair and propagate a profibrotic phenotype.
    explanation: >-
      Annual Review of Pathology 2022 review identifies the aberrant basaloid cell population as mechanistically
      relevant to IPF pathogenesis through disruption of normal epithelial repair.
  - reference: PMID:32832599
    reference_title: Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant
      basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers
      and are located at the edge of myofibroblast foci in the IPF lung.
    explanation: >-
      Single-cell and histologic localization demonstrate a disease-associated state, not causal lineage
      conversion.
  - reference: PMID:42182417
    reference_title: Chronic TGFβ1 Signaling Drives Aberrant Alveolar-Basaloid Metaplasia through a KRT17-Stratifin migratory complex.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using integrated single nucleus ATAC- and RNA-sequencing on human lungs and an in vitro model of
      dysplastic repair, we identify two distinct regenerative trajectories for alveolar type 2 (AT2)
      cells: a resolvable euplastic repair trajectory and a persistent, non-resolving dysplastic repair
      trajectory. The latter is governed by a spatially restricted ITGB6/TGFβ1/SMAD3 signaling axis in
      fibrotic regions of IPF lungs and in murine lungs characterized by chronic epithelial remodeling.
    explanation: >-
      Integrated human data and experimental dysplastic-repair models identify TGF-beta/SMAD3 regulation;
      human observational evidence alone does not establish temporal initiation.
  - reference: PMID:34969962
    reference_title: Human alveolar type 2 epithelium transdifferentiates into metaplastic KRT5(+) basal
      cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate
      into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo.
    explanation: >-
      Source for this node's statement that human AT2 cultures can undergo a basal transition under defined
      signaling conditions. The demonstration rests on primary and iPSC-derived human AT2 organoid co-culture
      with adult human lung mesenchyme, confirmed after xenotransplantation into injured mouse lung. Two
      constraints are worth recording: the transition is driven by mesenchymal TGF-beta1 and BMP antagonism
      rather than by AT2 senescence, and murine AT2 cells under identical conditions did not transdifferentiate,
      so mouse lineage-tracing results do not transfer to human disease.
- name: Epithelial and endothelial mesenchymal drift
  conforms_to: "mesenchymal_drift#Mesenchymal Drift of Differentiated Cells"
  description: >-
    Lung epithelial and endothelial cells in IPF lose lineage identity and up-regulate a mesenchymal gene
    program, the age-associated mesenchymal drift signature. In single-cell data this appears both as a
    shift in cell-type composition and as reprogramming within individual epithelial and endothelial
    cells, and a higher drift score in bronchoalveolar lavage tracks shorter survival. The signature is
    defined transcriptomically; whether the KRT17-positive aberrant basaloid population is one form of
    this drift or a separate injury-driven state is not established, so no edge links the two nodes.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: lung epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  - preferred_term: lung endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: mesenchymal drift (aberrant acquisition of mesenchymal identity)
    term:
      id: GO:0048762
      label: mesenchymal cell differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:41322283
    reference_title: "Inhibition of mesenchymal drift as a strategy for rejuvenation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In idiopathic pulmonary fibrosis (IPF), single-cell analyses reveal both compositional shifts and
      within-cell reprogramming of epithelial and endothelial populations.
    explanation: >-
      Review summary of the IPF single-cell results in Lu et al. 2025 (PMID:40816266), whose abstract does
      not itemize diseases. Graded HUMAN_CLINICAL for the human single-cell data it describes; the quote is
      the review's synthesis, not its own result.
  - reference: PMID:41322283
    reference_title: "Inhibition of mesenchymal drift as a strategy for rejuvenation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In a complementary bronchoalveolar lavage (BAL) gene-expression cohort of IPF patients (n = 132),
      stratification by MD-gene levels yielded median survival times of 2,498, 1,027/604, and 59 days
      across low, middle, and high MD groups, respectively
    explanation: >-
      Associates a higher drift score with shorter survival in an IPF cohort. This is a correlation and
      does not show that the drift causes progression.
  downstream:
  - target: Excessive extracellular matrix deposition
    description: >-
      Cells drifting toward a mesenchymal state express extracellular-matrix and profibrotic programs that
      add to the fibrotic matrix.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41322283
      reference_title: "Inhibition of mesenchymal drift as a strategy for rejuvenation."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        By eroding lineage identity and promoting fibrosis, MD disrupts organ integrity in the lung, liver,
        kidney, heart, and brain.
      explanation: >-
        Review statement that the drift promotes fibrosis in the lung, among other organs. Evidence source
        is OTHER because this is a review.
- name: Gut dysbiosis and microbial metabolite dysregulation
  mechanism_confidence: HYPOTHETICAL
  conforms_to: "gut_dysbiosis#Age-Associated Gut Microbiota Alteration"
  description: >-
    Altered gut microbial composition and metabolites have been associated with interstitial lung disease,
    and preclinical models suggest effects on immune responses and fibrosis. Directionality, specific
    mediators and independence from diet, disease severity and antifibrotic treatment remain unresolved
    in human IPF. This is an emerging modifier rather than an established universal upstream mechanism.
  role: amplifier
  locations:
  - preferred_term: large intestine
    term:
      id: UBERON:0000059
      label: large intestine
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:42294946
    reference_title: >-
      Potential Roles of Gut Microbiome and Metabolomes in Interstitial Lung Disease: Evidence across
      Preclinical and Clinical Research.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Accumulating evidence supports bidirectional gut-lung axis interactions potentially mediated by
      the microbiota. Alterations in the gut microbiome have been associated with the onset and severity
      of interstitial lung disease.
    explanation: >-
      Review-level evidence summarizes clinical associations and preclinical gut-lung mechanisms; it does
      not establish the specified causal sequence or direction in human IPF.
  - reference: PMID:42294946
    reference_title: >-
      Potential Roles of Gut Microbiome and Metabolomes in Interstitial Lung Disease: Evidence across
      Preclinical and Clinical Research.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Preclinical studies demonstrate that gut dysbiosis is associated with altered immune responses,
      increased pro-inflammatory cytokines, and enhanced fibrotic pathways, with mechanistic evidence
      suggesting the involvement of specific microbial metabolites (short-chain fatty acids, bile acids,
      and immune mediators.
    explanation: >-
      Review-level evidence summarizes clinical associations and preclinical gut-lung mechanisms; it does
      not establish the specified causal sequence or direction in human IPF.
  notes: >-
    Retained as an emerging associated modifier without directed downstream edges because the reviewed
    clinical evidence does not resolve causal direction or specific intermediates.
- name: Profibrotic macrophage recruitment and amplification
  description: >-
    Recruited monocyte-derived macrophages can amplify fibrosis after epithelial injury through CCR2-dependent
    pathways. Macrophage behavior changes with cell state and disease phase: some macrophage-derived signals
    promote resolution and fibroblast apoptosis. Neither a uniformly profibrotic macrophage role nor universal
    immune dependence follows from these models.
  conforms_to: "fibrotic_response#Inflammatory Recruitment and Amplification"
  role: amplifier
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  evidence:
  - reference: PMID:31922885
    reference_title: Diverse Injury Pathways Induce Alveolar Epithelial Cell CCL2/12, Which Promotes Lung Fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In contrast, mice with lung epithelial cell-specific deletion of CCL12 were protected from bleomycin-induced
      fibrosis and had expression of CCL2 and CCL7 similar to that of control mice treated with bleomycin.
      Deletion of CCL12 within AECs led to decreased recruitment of exudate macrophages.
    explanation: >-
      Epithelial CCL12 contributes to macrophage recruitment in this mouse injury model; global CCL12
      deletion was not protective and this is not universal immune necessity.
  - reference: PMID:34386777
    reference_title: Restoration of SIRT3 gene expression by airway delivery resolves age-associated persistent lung fibrosis in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, these findings reveal a novel role of SIRT3 in pro-resolution macrophage functions that
      restore susceptibility to apoptosis in fibroblasts via a FoxO3a-dependent mechanism.
    explanation: >-
      Macrophage-dependent effects can also favor resolution in the SIRT3 restoration model.
  downstream:
  - target: Excessive extracellular matrix deposition
    description: >-
      Bone-marrow-derived monocyte recruitment contributes to enhanced collagen deposition after bleomycin;
      the effect is model- and cell-state-dependent.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32253243
      reference_title: IRAK-M Regulates Monocyte Trafficking to the Lungs in Response to Bleomycin Challenge.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This finding prompted us to develop a competitive BM chimera model, which demonstrated that expression
        of BM-derived IRAK-M was necessary for monocyte trafficking into the lung and for subsequent enhanced
        collagen deposition.
      explanation: >-
        The bone-marrow chimera experiment links recruitment to collagen deposition in a defined injury
        context.
- name: IL-11 Autocrine Signalling in Lung Fibroblasts
  mechanism_confidence: PROVISIONAL
  description: >-
    IL-11 is increased in human IPF lungs and secreted by IPF fibroblasts. In cultured lung fibroblasts
    it promotes ERK-dependent, posttranscriptional myofibroblast conversion. Neutralizing IL-11 reverses
    fibrosis in a mouse model; efficacy in human IPF is not established by that experiment.
  conforms_to: "il11_erk_ampk_mtor_aging#IL-11 Receptor Signalling Activation"
  role: amplifier
  biological_scale: MOLECULAR
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  cell_types:
  - preferred_term: lung fibroblast
    term:
      id: CL:0002553
      label: fibroblast of lung
  biological_processes:
  - preferred_term: Interleukin-11-mediated signaling pathway
    term:
      id: GO:0038154
      label: interleukin-11-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:31554736
    reference_title: "Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      interleukin-11 (IL11) is up-regulated in the lung of patients with IPF, associated with disease
      severity, and IL-11 is secreted from IPF fibroblasts
    explanation: >-
      Establishes IL-11 up-regulation in patient IPF lung and its secretion by IPF fibroblasts, grounding
      this node in human disease. Evidence source is HUMAN_CLINICAL (patient lung tissue).
  - reference: PMID:31554736
    reference_title: "Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2+),
      collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent, posttranscriptional
      manner
    explanation: >-
      Directly evidences the IL-11 to ERK receptor-signalling arm driving fibroblast-to-myofibroblast
      conversion modeled by this node. Evidence source is IN_VITRO (cultured lung fibroblasts).
  - reference: PMID:31554736
    reference_title: "Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      anti-IL-11 treatment diminished lung inflammation and reversed lung fibrosis while inhibiting ERK
      and SMAD activation in mice
    explanation: >-
      Shows pharmacological IL-11 inhibition reverses lung fibrosis and lowers ERK activation in vivo,
      validating the drug-target link on this node. Evidence source is MODEL_ORGANISM (bleomycin mouse
      model).
  downstream:
  - target: Fibroblast activation and myofibroblast differentiation
    description: >-
      IL-11 activates ERK-dependent myofibroblast conversion and collagen secretion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31554736
      reference_title: "Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2+),
        collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent,
        posttranscriptional
        manner
      explanation: >-
        Directly evidences the IL-11 to ERK receptor-signalling arm driving fibroblast-to-myofibroblast
        conversion modeled by this node. Evidence source is IN_VITRO (cultured lung fibroblasts).
- name: Fibroblast activation and myofibroblast differentiation
  description: >-
    Resident mesenchymal cells become matrix-producing myofibroblasts in response to profibrotic mediators
    including TGF-beta and IL-11 and mechanical signals from matrix. Epithelial plasticity can alter the
    signaling environment, but coexpression of mesenchymal markers does not establish that epithelial
    cells are the source of pathogenic fibroblasts.
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  role: central_effector
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:35563849
    reference_title: "Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response,
      during which fibroblasts differentiate into myofibroblasts.
    explanation: This review directly supports fibroblast-to-myofibroblast differentiation as a core transition downstream of epithelial injury.
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: TGF-β is a critical cytokine that drives development of fibrosis.
    explanation: This review supports TGF-beta signaling as a central profibrotic pathway in IPF.
  downstream:
  - target: Excessive extracellular matrix deposition
    description: >-
      Activated myofibroblasts synthesize collagen and other matrix proteins.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31554736
      reference_title: "Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        IL-11 stimulates lung fibroblasts to become invasive actin alpha 2, smooth muscle-positive (ACTA2+),
        collagen-secreting myofibroblasts in an extracellular signal-regulated kinase (ERK)-dependent,
        posttranscriptional
        manner
      explanation: >-
        Directly evidences the IL-11 to ERK receptor-signalling arm driving fibroblast-to-myofibroblast
        conversion modeled by this node. Evidence source is IN_VITRO (cultured lung fibroblasts).
- name: Excessive extracellular matrix deposition
  description: >-
    Persistent matrix-producing mesenchymal cells deposit collagen and other extracellular matrix components.
    Progressive scarring stiffens and distorts the lung. Matrix-derived mechanical signals can reinforce
    fibroblast activation, without proving an irreversible autonomous scar state in every patient.
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  role: effector
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein
      folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast,
      deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis.
    explanation: This review links activated myofibroblasts directly to ECM deposition, architectural remodeling, and fibrosis in IPF.
  - reference: PMID:38232990
    reference_title: "The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact
      dynamically through multiple signalling pathways, including biochemical/molecular and mechanical
      signals, such as stiffness, affecting cell function and differentiation.
    explanation: >-
      Supports the mechano-transduction concept: matrix stiffness signals through integrin pathways to
      maintain fibroblast activation independently of soluble TGF-beta, providing a mechanistic basis
      for the feedback edge from ECM deposition back to fibroblast activation.
  downstream:
  - target: Architectural distortion and gas-exchange failure
    description: >-
      Interstitial scarring disrupts architecture and gas exchange and decreases compliance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32549377
      reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
        failure and death.
      explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
  - target: Fibroblast activation and myofibroblast differentiation
    description: >-
      Matrix mechanical signals can reinforce fibroblast activation; the review supports a feedback framework
      without quantifying its necessity in humans.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38232990
      reference_title: "The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact
        dynamically through multiple signalling pathways, including biochemical/molecular and mechanical
        signals, such as stiffness, affecting cell function and differentiation.
      explanation: >-
        Supports the mechano-transduction concept: matrix stiffness signals through integrin pathways
        to
        maintain fibroblast activation independently of soluble TGF-beta, providing a mechanistic basis
        for the feedback edge from ECM deposition back to fibroblast activation.
    hypothesis_groups:
    - feedback_loop_convergence_model
- name: Architectural distortion and gas-exchange failure
  description: >-
    Progressive interstitial scarring distorts alveolar units, decreases lung compliance and increases
    elastic recoil. Restricted lung expansion, loss of functioning alveolar-capillary surface and impaired
    oxygen transfer produce exertional limitation, hypoxemia and ultimately respiratory failure.
  conforms_to: "fibrotic_response#Architectural Distortion and Organ Dysfunction"
  role: consequence
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
      failure and death.
    explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
  downstream:
  - target: Dyspnea
    description: >-
      Reduced compliance and impaired gas exchange increase the burden of exertion and breathlessness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32549377
      reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
        failure and death.
      explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and
        commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing
      explanation: >-
        The diagnostic statement identifies these core clinical findings.
  - target: Exercise intolerance
    description: >-
      Fibrotic physiologic impairment limits exercise capacity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32274173
      reference_title: "Aerobic and breathing exercises improve dyspnea, exercise capacity and quality of life in idiopathic pulmonary fibrosis patients: systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea
        and limited exercise capacity.
      explanation: This systematic review explicitly identifies limited exercise capacity as a core functional limitation in IPF.
    - reference: PMID:32549377
      reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
        failure and death.
      explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
  - target: Hypoxemia
    description: >-
      Disrupted alveolar-capillary gas exchange impairs oxygenation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32549377
      reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
        failure and death.
      explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The recommendation for long-term oxygen therapy in patients with IPF and clinically significant
        resting hypoxemia is strong
      explanation: >-
        The guideline recognizes clinically significant hypoxemia and its treatment.
  - target: Respiratory failure
    description: >-
      Advanced architectural destruction produces severe gas-exchange failure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32549377
      reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
        failure and death.
      explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
  - target: Hypoxic pulmonary vasoconstriction and vascular remodeling
    description: >-
      Impaired ventilation and hypoxic alveolar regions can trigger compensatory vasoconstriction with
      maladaptive consequences when persistent.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31423872
      reference_title: Hypoxic Pulmonary Vasoconstriction and the Diffusing Capacity in Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Alveolar hypoxia causes pulmonary vasoconstriction to divert blood flow away from hypoxic regions
        to well‐ventilated areas to maintain the balance of ventilation/perfusion
      explanation: >-
        The initial response is compensatory; sustained widespread disease can contribute to vascular
        pressure elevation.
- name: Distal MUC5B overexpression and impaired clearance
  mechanism_confidence: PROVISIONAL
  description: >-
    The common MUC5B promoter risk allele increases pulmonary expression. Distal-airspace MUC5B overexpression
    impairs clearance and worsens persistent fibrosis after bleomycin in mice. This supplies a genetic
    susceptibility route distinct from telomere dysfunction; interaction with short leukocyte telomeres
    has been studied epidemiologically but its cellular mechanism remains unresolved.
  role: trigger
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:21506741
    reference_title: "A common MUC5B promoter polymorphism and pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia
      and idiopathic pulmonary fibrosis.
    explanation: This human case-control study identifies the MUC5B promoter variant rs35705950 as a major inherited susceptibility factor for IPF.
  - reference: PMID:30560893
    reference_title: Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, we demonstrate that Muc5b concentration in bronchoalveolar epithelia is related to impaired
      mucociliary clearance (MCC) and to the extent and persistence of bleomycin-induced lung fibrosis.
    explanation: >-
      Muc5b overexpression is a susceptibility amplifier in an injury model, not proof that this allele
      alone initiates fibrosis in humans.
  genes:
  - preferred_term: MUC5B
    term:
      id: hgnc:7516
      label: MUC5B
  downstream:
  - target: Excessive extracellular matrix deposition
    description: >-
      Impaired distal clearance increases the extent and persistence of fibrosis after epithelial injury;
      the intervening injury and repair steps are not resolved by the human association.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30560893
      reference_title: Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In mice, we demonstrate that Muc5b concentration in bronchoalveolar epithelia is related to impaired
        mucociliary clearance (MCC) and to the extent and persistence of bleomycin-induced lung fibrosis.
      explanation: >-
        Muc5b overexpression is a susceptibility amplifier in an injury model, not proof that this allele
        alone initiates fibrosis in humans.
- name: Surfactant dysfunction and epithelial proteostasis stress
  description: >-
    Rare surfactant variants predispose a subset of familial interstitial lung disease, sometimes classified
    as IPF. Misprocessing and endoplasmic-reticulum stress can compromise AT2 function, but variants differ:
    SP-A1 R219W-driven TGF-beta secretion is UPR dependent, whereas SP-C I73T and M71V secretion is largely
    UPR independent. L188Q SFTPC-induced ER stress increases bleomycin susceptibility without spontaneous
    fibrosis in one mouse model. Herpesvirus colocalization with UPR markers in human tissue does not
    establish viral causation.
  role: trigger
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:23926107
    reference_title: Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant
      proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in
      lung epithelial cell lines.
    explanation: >-
      Surfactant variants can promote TGF-beta secretion through variant-dependent pathways.
  - reference: PMID:21670280
    reference_title: Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain
      Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis
      was identified in the absence of a second profibrotic stimulus.
    explanation: >-
      The second-hit requirement is specific to this mutant-surfactant model.
  - reference: PMID:18390830
    reference_title: 'Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could
      contribute to disease progression.
    explanation: >-
      Human tissue supports pathway presence; the conditional language is retained.
  - reference: PMID:26792177
    reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated
      IIP/IPF, or IPF associated with lung adenocarcinoma
    explanation: >-
      A multigenerational family and secretion experiments support a rare SFTPA1-related subset; this
      is distinct from the common SP-A1 variant tested in the TGF-beta secretion study.
  genes:
  - preferred_term: SFTPC
    term:
      id: hgnc:10802
      label: SFTPC
  - preferred_term: SFTPA1
    term:
      id: hgnc:10798
      label: SFTPA1
  - preferred_term: SFTPA2
    term:
      id: hgnc:10799
      label: SFTPA2
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  downstream:
  - target: Repetitive alveolar epithelial injury and aberrant repair
    description: >-
      Variant-specific proteostasis stress sensitizes alveolar epithelium to injury and aberrant repair.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21670280
      reference_title: Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain
        Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis
        was identified in the absence of a second profibrotic stimulus.
      explanation: >-
        The second-hit requirement is specific to this mutant-surfactant model.
  - target: Persistent epithelial and mesenchymal TGF-beta signaling
    description: >-
      Variant expression increases secretion of latent TGF-beta in epithelial cell lines; dependence on
      the unfolded protein response differs by variant.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23926107
      reference_title: Lung fibrosis-associated surfactant protein A1 and C variants induce latent transforming growth factor β1 secretion in lung epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q)
        variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1
        in lung epithelial cell lines.
      explanation: >-
        Surfactant variants can promote TGF-beta secretion through variant-dependent pathways.
- name: Chronic canonical Wnt activation
  mechanism_confidence: PROVISIONAL
  description: >-
    Persistent canonical WNT/beta-catenin activation can shift AT2 cells toward senescence and impaired
    progenitor behavior in cultures and precision-cut lung slices. Acute and chronic stimulation differ.
    WNT5A did not reproduce the canonical senescence response in the cited assay; this does not exclude
    other profibrotic WNT5A actions.
  role: amplifier
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:32109549
    reference_title: Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Chronic canonical WNT/β-catenin activation for up to 7 days in primary ATII cells as well as alveolar
      epithelial cell lines induced a robust cellular senescence, whereas the non-canonical ligand WNT5A
      was not able to induce cellular senescence.
    explanation: >-
      Sustained canonical signaling induces senescence in these cultures; telomere independence was not
      directly tested.
  - reference: PMID:12707032
    reference_title: Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 18 of 20 cases of IPF/UIP investigated on serial sections, nuclear beta-catenin immunoreactivity
      and abnormal levels of cyclin-D1 and matrilysin were demonstrated in proliferative bronchiolar lesions
      (basal-cell hyperplasia, squamous metaplasia, bronchiolization, honeycombing)
    explanation: >-
      Immunohistochemistry places the pathway readout, nuclear beta-catenin with induction of the targets
      cyclin-D1 and matrilysin, in human IPF/UIP tissue, and the same study reports these features absent
      from normal lung and from other fibrosing pneumonias. It localizes activation to proliferative bronchiolar
      and honeycomb lesions rather than to alveolar type II cells specifically, so it grounds the node
      in the human disease without establishing the AT2 route tested in culture.
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  downstream:
  - target: AT2 cell senescence and SASP
    description: >-
      Sustained canonical Wnt stimulation induces senescence in alveolar epithelial models.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32109549
      reference_title: Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Chronic canonical WNT/β-catenin activation for up to 7 days in primary ATII cells as well as alveolar
        epithelial cell lines induced a robust cellular senescence, whereas the non-canonical ligand WNT5A
        was not able to induce cellular senescence.
      explanation: >-
        Sustained canonical signaling induces senescence in these cultures; telomere independence was
        not directly tested.
- name: AT2 fatty-acid oxidation impairment
  mechanism_confidence: PROVISIONAL
  description: >-
    FAO gene expression is reduced in human IPF alveolar epithelium. Experimental CPT1a deficiency produces
    mitochondrial dysfunction, lower SMAD7 and increased TGF-beta signaling, abnormal epithelial intermediates
    and increased injury susceptibility. These findings support a metabolic contribution to abnormal repair
    without proving that FAO loss is the initiating event in human IPF.
  role: amplifier
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:39927460
    reference_title: Regulation of lung progenitor plasticity and repair by fatty acid oxidation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a),
      the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant
      intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2.
    explanation: >-
      CPT1a perturbation changes epithelial metabolism and cell states in experimental models.
  - reference: PMID:39927460
    reference_title: Regulation of lung progenitor plasticity and repair by fatty acid oxidation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing
      lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells,
      airway secretory cells, and senescence.
    explanation: >-
      AT2-specific metabolic deficiency amplifies injury-associated fibrosis; it is not an established
      monogenic cause of human IPF.
  genes:
  - preferred_term: CPT1A
    term:
      id: hgnc:2328
      label: CPT1A
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  downstream:
  - target: Aberrant basaloid cell emergence
    description: >-
      Metabolic perturbation promotes aberrant intermediate states bearing basaloid markers; these markers
      do not establish identity with every human basaloid population.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39927460
      reference_title: Regulation of lung progenitor plasticity and repair by fatty acid oxidation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a),
        the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant
        intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2.
      explanation: >-
        CPT1a perturbation changes epithelial metabolism and cell states in experimental models.
  - target: AT2 cell senescence and SASP
    description: >-
      AT2 CPT1a deficiency increases senescence-marker-positive epithelial cells during experimental fibrosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39927460
      reference_title: Regulation of lung progenitor plasticity and repair by fatty acid oxidation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing
        lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells,
        airway secretory cells, and senescence.
      explanation: >-
        AT2-specific metabolic deficiency amplifies injury-associated fibrosis; it is not an established
        monogenic cause of human IPF.
- name: Self-DNA sensing through epithelial cGAS
  mechanism_confidence: PROVISIONAL
  description: >-
    Mitochondrial DNA accumulation in cytosol and extracellular medium accompanies stressed IPF epithelial
    cultures. cGAS inhibition, RNA interference and DNase experiments support self-DNA-dependent senescence
    amplification. The study does not demonstrate obligatory STING activation or a requirement for recruited
    immune cells in every fibrosis model.
  role: amplifier
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:34524912
    reference_title: 'A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, ectopic mtDNA augmented cGAS-dependent senescence of Ctrl-AECs, whereas DNAse I treatment
      diminished IPF-AEC senescence.
    explanation: >-
      Self-DNA perturbations and cGAS inhibition support senescence amplification in cultured epithelial
      cells.
  genes:
  - preferred_term: CGAS
    term:
      id: hgnc:21367
      label: CGAS
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  downstream:
  - target: AT2 cell senescence and SASP
    description: >-
      Self-DNA sensing augments epithelial senescence in primary cultures and cell-line perturbations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34524912
      reference_title: 'A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, ectopic mtDNA augmented cGAS-dependent senescence of Ctrl-AECs, whereas DNAse I treatment
        diminished IPF-AEC senescence.
      explanation: >-
        Self-DNA perturbations and cGAS inhibition support senescence amplification in cultured epithelial
        cells.
- name: Persistent epithelial and mesenchymal TGF-beta signaling
  description: >-
    Epithelial and mesenchymal TGF-beta signaling promotes myofibroblast differentiation and dysplastic
    epithelial repair. In a bleomycin-exposed organoid system an epithelial autocrine loop sustains a
    profibrotic secretory state. Sustained signaling also redirects human AT2 repair toward basaloid intermediates;
    this is distinct from epithelial conversion into fibroblasts.
  role: amplifier
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:37653024
    reference_title: Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast
      differentiation.
    explanation: >-
      Within the tested organoid system, epithelial TGF-beta mediates fibroblast differentiation; the
      exclusivity is assay-specific.
  - reference: PMID:37653024
    reference_title: Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular
      system in non-inflammatory lung fibrogenesis.
    explanation: >-
      Perturbations in immune-cell-free epithelial-fibroblast organoids support a local autocrine loop.
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  downstream:
  - target: AT2 cell senescence and SASP
    description: >-
      Autocrine TGF-beta sustains the profibrotic AT2-lineage state in the tested organoid model.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37653024
      reference_title: Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular
        system in non-inflammatory lung fibrogenesis.
      explanation: >-
        Perturbations in immune-cell-free epithelial-fibroblast organoids support a local autocrine loop.
    hypothesis_groups:
    - feedback_loop_convergence_model
  - target: Fibroblast activation and myofibroblast differentiation
    description: >-
      Paracrine epithelial TGF-beta induces myofibroblast differentiation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37653024
      reference_title: Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast
        differentiation.
      explanation: >-
        Within the tested organoid system, epithelial TGF-beta mediates fibroblast differentiation; the
        exclusivity is assay-specific.
  - target: Aberrant basaloid cell emergence
    description: >-
      Persistent TGF-beta/SMAD3 signaling promotes dysplastic transitional-cell programs, including KRT17
      and stratifin.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42182417
      reference_title: Chronic TGFβ1 Signaling Drives Aberrant Alveolar-Basaloid Metaplasia through a KRT17-Stratifin migratory complex.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using integrated single nucleus ATAC- and RNA-sequencing on human lungs and an in vitro model
        of dysplastic repair, we identify two distinct regenerative trajectories for alveolar type 2 (AT2)
        cells: a resolvable euplastic repair trajectory and a persistent, non-resolving dysplastic repair
        trajectory. The latter is governed by a spatially restricted ITGB6/TGFβ1/SMAD3 signaling axis
        in fibrotic regions of IPF lungs and in murine lungs characterized by chronic epithelial remodeling.
      explanation: >-
        Integrated human data and experimental dysplastic-repair models identify TGF-beta/SMAD3 regulation;
        human observational evidence alone does not establish temporal initiation.
- name: Senescent myofibroblast persistence and apoptosis resistance
  description: >-
    Aging-associated myofibroblasts can fail to dedifferentiate and become resistant to apoptosis. NOX4/NRF2
    redox imbalance, sustained MyoD and BCL-2-dependent survival support persistence in experimental systems.
    Human IPF fibroblasts share aspects of these states. Senescence therefore contributes through mesenchymal
    persistence as well as epithelial dysfunction.
  role: amplifier
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:41764163
    reference_title: Conditional BCL-2 Expression in Fibroblasts Promotes Persistent Pulmonary Fibrosis which is Reversible by Therapeutic BCL-2 Inhibition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we show that prevention of PDGFRα+ fibroblast apoptosis by conditional BCL-2 expression leads
      to the emergence and persistence of senescent, pro-fibrotic fibroblasts along with enduring, pathologic
      fibrotic lung remodeling.
    explanation: >-
      Conditional anti-apoptotic signaling demonstrates a fibroblast persistence route in mice, not universal
      BCL-2 dependence in humans.
  - reference: PMID:31962055
    reference_title: Impaired Myofibroblast Dedifferentiation Contributes to Nonresolving Fibrosis in Aging.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrated that nonsenescent lung myofibroblasts maintained the capacity for dedifferentiation,
      whereas senescent/IPF myofibroblasts exhibited an impaired capacity for dedifferentiation.
    explanation: >-
      Cultured IPF fibroblasts show impaired fate reversal.
  - reference: PMID:24718857
    reference_title: Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nox4 mediated senescence and apoptosis resistance in IPF fibroblasts.
    explanation: >-
      Experimental fibroblast perturbations support redox-dependent persistence.
  downstream:
  - target: Excessive extracellular matrix deposition
    description: >-
      Failure of myofibroblast clearance maintains matrix-producing cells and persistent fibrotic remodeling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41764163
      reference_title: Conditional BCL-2 Expression in Fibroblasts Promotes Persistent Pulmonary Fibrosis which is Reversible by Therapeutic BCL-2 Inhibition.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we show that prevention of PDGFRα+ fibroblast apoptosis by conditional BCL-2 expression
        leads to the emergence and persistence of senescent, pro-fibrotic fibroblasts along with enduring,
        pathologic fibrotic lung remodeling.
      explanation: >-
        Conditional anti-apoptotic signaling demonstrates a fibroblast persistence route in mice, not
        universal BCL-2 dependence in humans.
- name: Age-associated endothelial repair failure
  mechanism_confidence: PROVISIONAL
  description: >-
    Endothelial ERG dysregulation and capillary cell-state changes accompany aging and fibrotic repair.
    Conditional endothelial ERG loss impairs fibrosis resolution in mice and enhances paracrine fibroblast
    activation in culture. Human transcriptional overlap supports relevance but does not establish an
    independent initiating vascular lesion in all IPF.
  role: amplifier
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:35879310
    reference_title: Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss of endothelial ERG ... impairs lung fibrosis resolution in young mice in vivo.
    explanation: >-
      Conditional endothelial ERG loss impairs fibrosis resolution in mice; the separate in-vitro edge
      quotes the fibroblast-activation finding.
  downstream:
  - target: Fibroblast activation and myofibroblast differentiation
    description: >-
      Loss of endothelial ERG enhances paracrine fibroblast activation in culture.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35879310
      reference_title: Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Loss of endothelial ERG enhances paracrine fibroblast activation in vitro
      explanation: >-
        The specific cellular perturbation supports endothelial-to-fibroblast signaling.
- name: Hypoxic pulmonary vasoconstriction and vascular remodeling
  description: >-
    Disturbed ventilation-perfusion and alveolar hypoxia can provoke pulmonary vasoconstriction. Persistent
    vasoconstriction and vascular remodeling contribute to pulmonary hypertension, alongside cytokine
    and growth-factor effects. Pulmonary hypertension severity is not determined solely by the extent
    of fibrosis.
  role: consequence
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:31423872
    reference_title: Hypoxic Pulmonary Vasoconstriction and the Diffusing Capacity in Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, continuous HPV‐related vasoconstriction can induce shear stress–related vascular remodeling
    explanation: >-
      The review describes a pathway from prolonged hypoxic vasoconstriction to vascular remodeling; fibrosis
      extent alone does not determine pulmonary pressure.
  downstream:
  - target: Pulmonary hypertension
    description: >-
      Sustained vascular constriction and remodeling increase pulmonary vascular resistance and pressure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31423872
      reference_title: Hypoxic Pulmonary Vasoconstriction and the Diffusing Capacity in Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        However, continuous HPV‐related vasoconstriction can induce shear stress–related vascular remodeling
      explanation: >-
        The review describes a pathway from prolonged hypoxic vasoconstriction to vascular remodeling;
        fibrosis extent alone does not determine pulmonary pressure.
phenotypes:
- category: Respiratory
  name: Dyspnea
  description: Persistent exertional breathlessness is the dominant presenting symptom in most patients.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:32274173
    reference_title: "Aerobic and breathing exercises improve dyspnea, exercise capacity and quality of life in idiopathic pulmonary fibrosis patients: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea
      and limited exercise capacity.
    explanation: This systematic review explicitly identifies dyspnea as a major symptomatic burden in IPF.
- category: Respiratory
  name: Exercise intolerance
  description: Progressive loss of ventilatory reserve and gas exchange limits exertional capacity.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:32274173
    reference_title: "Aerobic and breathing exercises improve dyspnea, exercise capacity and quality of life in idiopathic pulmonary fibrosis patients: systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with significant dyspnea
      and limited exercise capacity.
    explanation: This systematic review explicitly identifies limited exercise capacity as a core functional limitation in IPF.
- category: Respiratory
  name: Respiratory failure
  description: End-stage restrictive lung disease leads to irreversible gas exchange failure.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
      failure and death.
    explanation: This review directly links progressive architectural distortion in IPF to respiratory failure.
- name: Cough
  category: Respiratory
  description: >-
    Persistent cough is a common presenting symptom. It may arise through several airway and sensory mechanisms;
    the reviewed sources do not identify a single obligatory mediator.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and
      commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing
    explanation: >-
      The diagnostic statement identifies these core clinical findings.
  notes: >-
    Clinical association is supported. No directed mechanism edge is imposed because the reviewed sources
    do not identify its specific causal mediation.
- name: Inspiratory crackles
  category: Respiratory
  description: >-
    Bibasilar inspiratory crackles are characteristic on auscultation.
  phenotype_term:
    preferred_term: Inspiratory crackles
    term:
      id: HP:0031996
      label: Inspiratory crackles
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and
      commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing
    explanation: >-
      The diagnostic statement identifies these core clinical findings.
  notes: >-
    Clinical association is supported. No directed mechanism edge is imposed because the reviewed sources
    do not identify its specific causal mediation.
- name: Clubbing of fingers
  category: Respiratory
  description: >-
    Digital clubbing can accompany IPF; it is neither universal nor specific and its causal mediator is
    not established by the cited guideline.
  phenotype_term:
    preferred_term: Clubbing of fingers
    term:
      id: HP:0100759
      label: Clubbing of fingers
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IPF should be considered in all adult patients with unexplained chronic exertional dyspnea, and
      commonly presents with cough, bibasilar inspiratory crackles, and finger clubbing
    explanation: >-
      The diagnostic statement identifies these core clinical findings.
  notes: >-
    Clinical association is supported. No directed mechanism edge is imposed because the reviewed sources
    do not identify its specific causal mediation.
- name: Hypoxemia
  category: Respiratory
  description: >-
    Impaired alveolar gas exchange causes oxygen desaturation, initially often during exertion and later
    potentially at rest.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommendation for long-term oxygen therapy in patients with IPF and clinically significant
      resting hypoxemia is strong
    explanation: >-
      The guideline recognizes clinically significant hypoxemia and its treatment.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/
    reference_title: Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypoxemia with exertion is usually one of the earliest signs. With disease progression, hypoxemia
      occurs at rest.
    explanation: >-
      GeneReviews describes pulmonary-fibrosis physiology; the broader inherited-PF context is applicable
      to the fibrotic clinical manifestation, not evidence of an IPF-specific etiology.
- name: Restrictive ventilatory defect
  category: Respiratory
  description: >-
    Fibrotic loss of compliance restricts lung expansion and reduces vital capacity; FVC and diffusing
    capacity track physiologic impairment.
  phenotype_term:
    preferred_term: Restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: PMID:32549377
    reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
      failure and death.
    explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
  - reference: PMID:24836310
    reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary end point was the annual rate of decline in forced vital capacity (FVC).
    explanation: >-
      The pivotal IPF nintedanib trials used annual FVC decline as the primary physiologic endpoint.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/
    reference_title: Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Degradation of pulmonary function occurs over time, with progressive decline of forced vital capacity
      and diffusion capacity.
    explanation: >-
      The chapter supports longitudinal restrictive and gas-transfer impairment across fibrotic lung disease.
  reports_on:
  - target: Architectural distortion and gas-exchange failure
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: >-
      Restrictive physiology is a functional readout of fibrotic architectural impairment, rather than
      a molecular initiating event.
    evidence:
    - reference: PMID:32549377
      reference_title: "Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The compromised architecture leads to disturbed gas exchange, decreased lung compliance, and respiratory
        failure and death.
      explanation: This review directly supports structural distortion as the mechanism linking fibrosis to respiratory failure and mortality.
- name: Pulmonary hypertension
  category: Cardiovascular
  description: >-
    Pulmonary hypertension may complicate fibrotic lung disease and worsen functional limitation. It is
    not equivalent to primary pulmonary arterial hypertension.
  phenotype_term:
    preferred_term: Pulmonary hypertension in fibrotic lung disease
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  notes: >-
    The HPO term denotes elevated pulmonary arterial pressure here; this is group 3 pulmonary hypertension
    associated with lung disease, not a claim of group 1 PAH.
  evidence:
  - reference: PMID:31423872
    reference_title: Hypoxic Pulmonary Vasoconstriction and the Diffusing Capacity in Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although many patients with IPF‐PH have only mild PH, some have severe PH, and their prognosis remains
      poor.
    explanation: >-
      The review documents pulmonary hypertension complicating IPF.
biochemical:
- name: Forced Vital Capacity
  loinc_term:
    id: LOINC:19870-5
    label: Forced vital capacity [Volume] Respiratory system
  presence: Often decreased with restrictive disease; treatment benefit is commonly a slower decline rather than restoration to normal.
  context: >-
    Pulmonary function test readout used to measure restrictive ventilatory impairment and treatment response
    in pulmonary fibrosis.
  notes: >-
    The LOINC code is the method-less FVC volume, the quantity the trials cited below report
    the annual decline of; FVC as a fraction of predicted (LOINC:19872-1), the form the GAP
    index uses, is bound on the pulmonary function diagnosis row.
  biomarker_term:
    preferred_term: Forced Vital Capacity
    term:
      id: NCIT:C111361
      label: Forced Vital Capacity
  synonyms:
  - FVC
  readouts:
  - target: Architectural distortion and gas-exchange failure
    relationship: PHARMACODYNAMIC_MARKER_OF
    direction: NEGATIVE
    endpoint_context: REGULATORY_SURROGATE
    regulatory_endpoint_refs:
    - FDA-SE-adult-noncancer-098
    interpretation: >-
      Higher or less-declining FVC indicates less restrictive physiologic impairment from fibrotic architectural
      distortion; treatment-induced slowing of FVC decline reports pharmacodynamic slowing of disease
      progression.
    evidence:
    - reference: PMID:24836310
      reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is
        consistent with a slowing of disease progression;
      explanation: >-
        The INPULSIS trials link treatment-induced slowing of FVC decline to slowed IPF disease progression.
  evidence:
  - reference: PMID:24836310
    reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary end point was the annual rate of decline in forced vital capacity (FVC).
    explanation: >-
      The pivotal IPF nintedanib trials used annual FVC decline as the primary physiologic endpoint.
- name: Circulating GDF15
  presence: Increased
  context: >-
    Candidate marker of epithelial stress and disease severity; not an established treatment-selection
    test.
  specificity: >-
    Not specific to IPF, AT2 senescence or telomere dysfunction.
  evidence:
  - reference: PMID:31432710
    reference_title: GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and
      survival in multiple independent cohorts.
    explanation: >-
      Human cohorts support a stress-associated prognostic biomarker; this does not prove a profibrotic
      causal action or IPF-specific senescence burden assay.
  readouts:
  - target: Architectural distortion and gas-exchange failure
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Circulating GDF15 associates with severity and survival, while epithelial stress is a proposed biological
      source. Association does not establish causal mediation.
    evidence:
    - reference: PMID:31432710
      reference_title: GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        circulating concentrations of GDF15 are markedly elevated and correlate with disease severity
        and survival in multiple independent cohorts.
      explanation: >-
        Human cohorts support a stress-associated prognostic biomarker; this does not prove a profibrotic
        causal action or IPF-specific senescence burden assay.
  biomarker_term:
    preferred_term: GDF15
    term:
      id: NCIT:C34026
      label: Growth/Differentiation Factor 15
- name: Serum KL-6
  biomarker_term:
    preferred_term: KL-6 antigen
    term:
      id: NCIT:C178663
      label: KL-6 Antigen
  presence: INCREASED
  context: Regenerating type II pneumocytes produce the MUC1-associated KL-6 antigen. Elevated serum levels can correlate with prognosis but are nonspecific; they neither establish IPF alone nor prove a validated surrogate for treatment benefit.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Serum levels of KL-6 have been shown to be elevated in patients with IPF, and these levels may correlate with increased risk of subsequent mortality
    explanation: The guideline summarizes observational serum associations, not a disease-specific diagnostic cutoff or a validated therapeutic surrogate.
  - reference: PMID:30168753
    reference_title: Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs.
    explanation: The diagnostic guideline prevents using a nonspecific serum biomarker alone to distinguish IPF from other interstitial lung diseases.
- name: MMP-7 in plasma and bronchoalveolar lavage
  biomarker_term:
    preferred_term: MMP-7
    term:
      id: NCIT:C98113
      label: Matrilysin
  presence: INCREASED
  context: MMP-7 abundance is associated with IPF and may correlate with disease severity. Circulating or lavage measurements do not directly identify the cellular source, demonstrate a required causal protease mechanism or establish response-surrogate validity.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Studies of plasma and BAL matrix metalloproteinase (MMP) levels suggest that MMP1 and MMP7 are increased in patients with IPF, and MMP7 levels may correlate with disease severity
    explanation: The guideline supports the biochemical association while preserving uncertainty about clinical use and mechanism.
  - reference: PMID:30168753
    reference_title: Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs.
    explanation: The diagnostic guideline prevents using a nonspecific serum biomarker alone to distinguish IPF from other interstitial lung diseases.
genetic:
- name: MUC5B
  association: Associated
  gene_term:
    preferred_term: MUC5B
    term:
      id: hgnc:7516
      label: MUC5B
  notes: MUC5B is a major susceptibility gene in IPF, and the rs35705950 promoter polymorphism is associated with disease risk and increased pulmonary MUC5B expression.
  evidence:
  - reference: PMID:21506741
    reference_title: "A common MUC5B promoter polymorphism and pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia
      and idiopathic pulmonary fibrosis.
    explanation: This human case-control study identifies the MUC5B promoter variant rs35705950 as a major inherited susceptibility factor for IPF.
  - reference: PMID:33965873
    reference_title: "Molecular pathways in idiopathic pulmonary fibrosis pathogenesis: Transcending barriers to optimally targeted pharmacotherapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Key among these were the up-regulation of TGFBI, MMP7, TNF, ADAM12, activation of immune co-stimulatory
      markers, toll-like receptors, and increased expression of the IPF-related gene MUC5B in both minimal
      and established fibrotic regions of the lungs.
    explanation: This review specifically identifies increased MUC5B expression as part of the molecular program present in fibrotic IPF lung tissue.
  relationship_type: RISK_FACTOR
- name: TERT
  association: Associated
  gene_term:
    preferred_term: TERT
    term:
      id: hgnc:11730
      label: TERT
  notes: >-
    Rare pathogenic variants impair telomerase function and predispose to familial pulmonary fibrosis,
    sometimes classified as IPF, with age-dependent incomplete penetrance. Leukocyte telomere shortening
    supports systemic telomere dysfunction; the clinical cohort does not directly measure AT2-specific
    telomere length or establish a uniform progression rate.
  evidence:
  - reference: PMID:35078193
    reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10,
      and 1 NHP2)
    explanation: >-
      Greek national cohort identifies TERT as the most frequently mutated telomere-related gene in heritable
      IPF, establishing its role as a major genetic determinant of familial pulmonary fibrosis.
  - reference: PMID:33808277
    reference_title: "Telomeres in Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations,
      regardless of underlying diagnosis.
    explanation: >-
      Review confirms that TERT and other telomere gene mutations confer worse prognosis in IPF, consistent
      with the mechanistic model of AT2 telomere dysfunction accelerating senescence.
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant predisposition
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Describes the heterozygous adult pulmonary-fibrosis predisposition subset. Age-dependent penetrance
      and variable ILD phenotype limit prediction; some genes also cause distinct recessive syndromes.
    evidence:
    - reference: PMID:35078193
      reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10,
        and 1 NHP2)
      explanation: >-
        Greek national cohort identifies TERT as the most frequently mutated telomere-related gene in
        heritable
        IPF, establishing its role as a major genetic determinant of familial pulmonary fibrosis.
- name: TERC
  association: Associated
  gene_term:
    preferred_term: TERC
    term:
      id: hgnc:11727
      label: TERC
  notes: >-
    Rare pathogenic variants impair telomerase function and predispose to familial pulmonary fibrosis,
    sometimes classified as IPF, with age-dependent incomplete penetrance. Leukocyte telomere shortening
    supports systemic telomere dysfunction; the clinical cohort does not directly measure AT2-specific
    telomere length or establish a uniform progression rate.
  evidence:
  - reference: PMID:35078193
    reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10,
      and 1 NHP2)
    explanation: >-
      Greek national cohort identifies TERC as the second most frequently mutated telomere-related gene
      in heritable IPF.
  - reference: PMID:33808277
    reference_title: "Telomeres in Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A number of rare genetic mutations have been identified in genes encoding for components of the
      telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component
      (TERC), in familial and, less frequently, in sporadic fibrotic ILDs.
    explanation: >-
      Review confirms TERC mutations as a cause of familial and sporadic fibrotic ILD, consistent with
      the AT2 telomere shortening to senescence mechanistic model.
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant predisposition
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Describes the heterozygous adult pulmonary-fibrosis predisposition subset. Age-dependent penetrance
      and variable ILD phenotype limit prediction; some genes also cause distinct recessive syndromes.
    evidence:
    - reference: PMID:35078193
      reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10,
        and 1 NHP2)
      explanation: >-
        Greek national cohort identifies TERC as the second most frequently mutated telomere-related gene
        in heritable IPF.
- name: RTEL1
  association: Associated
  gene_term:
    preferred_term: RTEL1
    term:
      id: hgnc:15888
      label: RTEL1
  notes: >-
    Monoallelic variants in RTEL1 (regulator of telomere elongation helicase 1) impair DNA helicase activity
    at telomeres and have been identified in heritable IPF cohorts.
  evidence:
  - reference: PMID:35078193
    reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10,
      and 1 NHP2)
    explanation: >-
      Greek national cohort identifies RTEL1 as a telomere-related gene mutated in heritable IPF, extending
      the genetic architecture beyond TERT/TERC to include DNA helicase function.
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant predisposition
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Describes the heterozygous adult pulmonary-fibrosis predisposition subset. Age-dependent penetrance
      and variable ILD phenotype limit prediction; some genes also cause distinct recessive syndromes.
    evidence:
    - reference: PMID:35078193
      reference_title: "Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10,
        and 1 NHP2)
      explanation: >-
        Greek national cohort identifies RTEL1 as a telomere-related gene mutated in heritable IPF, extending
        the genetic architecture beyond TERT/TERC to include DNA helicase function.
- name: PARN
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PARN
    term:
      id: hgnc:8609
      label: PARN
  notes: >-
    Rare damaging variants predispose to telomere-related pulmonary fibrosis with incomplete penetrance.
    This spectrum includes IPF and other fibrotic ILD diagnoses.
  evidence:
  - reference: PMID:25848748
    reference_title: Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic
      inheritance of short telomeres in family members.
    explanation: >-
      Human pedigrees link rare variants to telomere dysfunction and familial pulmonary fibrosis.
  - reference: PMID:28099038
    reference_title: An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide
      significant contributors to sporadic IPF.
    explanation: >-
      Rare-variant enrichment extends the association beyond recognized familial disease.
  inheritance:
  - name: Autosomal dominant predisposition
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Describes the heterozygous adult pulmonary-fibrosis predisposition subset. Age-dependent penetrance
      and variable ILD phenotype limit prediction; some genes also cause distinct recessive syndromes.
    evidence:
    - reference: PMID:25848748
      reference_title: Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic
        inheritance of short telomeres in family members.
      explanation: >-
        Human pedigrees link rare variants to telomere dysfunction and familial pulmonary fibrosis.
- name: SFTPC
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SFTPC
    term:
      id: hgnc:10802
      label: SFTPC
  notes: Rare pathogenic variants cause surfactant-related ILD with variable onset and imaging, including some familial cases classified as IPF. Variant-specific trafficking and stress mechanisms differ.
  evidence:
  - reference: PMID:11991887
    reference_title: Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We show that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred
    explanation: Segregation of a heterozygous L188Q variant with familial fibrosis supports a pathogenic SFTPC relationship in a defined kindred; affected adults had UIP and affected children had cellular NSIP. This does not make SFTPC a common cause of sporadic IPF.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Pathogenic variants in the surfactant metabolism genes (SFTPA1, SFTPA2, SFTPC) are typically missense variants that lead to increased endoplasmic reticulum stress.
    explanation: GeneReviews identifies pathogenic SFTPC variants as a cause of surfactant-related fibrosis predisposition; the precise mechanism depends on the variant.
  inheritance:
  - name: Autosomal dominant inheritance with variable expression
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: Heterozygous pathogenic SFTPC variants can produce surfactant-related ILD from infancy to adulthood, including adult UIP/fibrosis. Reduced, age-related penetrance and variable expression prevent prediction of an individual carrier’s onset or lung phenotype; the variant-transmission probability is not the disease probability.
    evidence:
    - reference: PMID:15133475
      reference_title: Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The inheritance pattern of usual interstitial pneumonia is consistent with autosomal dominant inheritance with variable expression.
      explanation: The SFTPC L188Q family study directly describes dominant transmission with variable expression across adult UIP and childhood NSIP.
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Because predisposition to pulmonary fibrosis is associated with reduced penetrance and intrafamilial clinical variability, the age of onset and clinical manifestations in a sib who inherits a familial pathogenic variant cannot be predicted.
      explanation: The genetic-counseling section supports incomplete penetrance and variable phenotype; Table 1 includes SFTPC among the autosomal dominant surfactant-related causes.
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
      reference_title: https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Each child of an individual with a germline pathogenic variant associated with predisposition to pulmonary fibrosis has a 50% chance of inheriting the pathogenic variant.
      explanation: The 50% probability concerns inheritance of a heterozygous pathogenic variant, not a 50% lifetime probability of clinically diagnosed IPF.
- name: SFTPA2
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SFTPA2
    term:
      id: hgnc:10799
      label: SFTPA2
  notes: >-
    Rare pathogenic variants cause familial fibrosis with lung adenocarcinoma susceptibility; this is
    a specific genetic subset, not a universal IPF mechanism.
  evidence:
  - reference: PMID:19100526
    reference_title: Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data are consistent with SFTPA2 germline mutations that interfere with protein trafficking
      and cause familial IPF and lung cancer.
    explanation: >-
      Rare pathogenic variants cause familial fibrosis with lung adenocarcinoma susceptibility; this is
      a specific genetic subset, not a universal IPF mechanism.
  - reference: PMID:40491472
    reference_title: Penetrance of interstitial lung disease and lung cancer in carriers of SFTPA1 or SFTPA2 pathogenic variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, heterozygous germline pathogenic or likely pathogenic variants (PGVs) in SFTPA1 and
      SFTPA2, which encode surfactant proteins SP-A1 and SP-A2, can result in a range of outcomes from
      asymptomatic cases to severe lung fibrosis and adenocarcinoma, with high mortality risks
    explanation: >-
      The pedigree study supports age-dependent variable disease expression. Pooled gene estimates, missing
      exposure data and competing-risk limitations prevent treating its penetrance numbers as universal
      IPF risks.
  inheritance:
  - name: Autosomal dominant predisposition
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Describes the heterozygous adult pulmonary-fibrosis predisposition subset. Age-dependent penetrance
      and variable ILD phenotype limit prediction; some genes also cause distinct recessive syndromes.
    evidence:
    - reference: PMID:19100526
      reference_title: Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These data are consistent with SFTPA2 germline mutations that interfere with protein trafficking
        and cause familial IPF and lung cancer.
      explanation: >-
        Rare pathogenic variants cause familial fibrosis with lung adenocarcinoma susceptibility; this
        is
        a specific genetic subset, not a universal IPF mechanism.
- name: SFTPA1
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SFTPA1
    term:
      id: hgnc:10798
      label: SFTPA1
  notes: >-
    Rare pathogenic variants can cause familial interstitial pneumonia/IPF with lung adenocarcinoma susceptibility.
    Evidence comes from limited pedigrees and functional secretion studies; it is not interchangeable
    with SFTPA2 or with common SFTPA1 polymorphisms.
  evidence:
  - reference: PMID:26792177
    reference_title: Germline SFTPA1 mutation in familial idiopathic interstitial pneumonia and lung cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated
      IIP/IPF, or IPF associated with lung adenocarcinoma
    explanation: >-
      A multigenerational family and secretion experiments support a rare SFTPA1-related subset; this
      is distinct from the common SP-A1 variant tested in the TGF-beta secretion study.
  - reference: PMID:40491472
    reference_title: Penetrance of interstitial lung disease and lung cancer in carriers of SFTPA1 or SFTPA2 pathogenic variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, heterozygous germline pathogenic or likely pathogenic variants (PGVs) in SFTPA1 and
      SFTPA2, which encode surfactant proteins SP-A1 and SP-A2, can result in a range of outcomes from
      asymptomatic cases to severe lung fibrosis and adenocarcinoma, with high mortality risks
    explanation: >-
      The pedigree study supports age-dependent variable disease expression. Pooled gene estimates, missing
      exposure data and competing-risk limitations prevent treating its penetrance numbers as universal
      IPF risks.
  inheritance:
  - name: Autosomal dominant predisposition
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    description: >-
      Describes heterozygous pathogenic-variant families with variable age at onset and phenotype.
    evidence:
    - reference: PMID:40491472
      reference_title: Penetrance of interstitial lung disease and lung cancer in carriers of SFTPA1 or SFTPA2 pathogenic variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Specifically, heterozygous germline pathogenic or likely pathogenic variants (PGVs) in SFTPA1
        and SFTPA2, which encode surfactant proteins SP-A1 and SP-A2, can result in a range of outcomes
        from asymptomatic cases to severe lung fibrosis and adenocarcinoma, with high mortality risks
      explanation: >-
        The pedigree study supports age-dependent variable disease expression. Pooled gene estimates,
        missing exposure data and competing-risk limitations prevent treating its penetrance numbers as
        universal IPF risks.
diagnosis:
- name: Lung biopsy for histopathologic pattern
  description: >-
    Tissue sampling is considered when clinical and imaging assessment cannot establish a sufficiently
    confident diagnosis and procedural risk is acceptable. Transbronchial cryobiopsy is a conditional
    alternative to surgical biopsy in centers with appropriate expertise; biopsy is not mandatory for
    every patient without definite HRCT honeycombing.
  diagnosis_term:
    preferred_term: biopsy of lung
    term:
      id: NCIT:C51748
      label: Lung Biopsy
  results: Histopathologic pattern used to establish or exclude usual interstitial pneumonia.
  evidence:
  - reference: PMID:35486072
    reference_title: "Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise."
    explanation: The ATS/ERS/JRS/ALAT guideline conditionally recommends transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy where expertise exists.

- name: High-resolution chest CT
  diagnosis_term:
    preferred_term: High Resolution Computed Tomography
    term:
      id: NCIT:C20644
      label: High Resolution Computed Tomography
  description: >-
    Evaluate subpleural and basal reticulation, traction bronchiectasis and honeycombing, together with
    features suggesting an alternative diagnosis. Integrate the imaging pattern with clinical context.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      UIP is characterized on HRCT by the presence of reticular opacities, often associated with traction
      bronchiectasis
    explanation: >-
      The guideline describes a key radiologic UIP pattern.
- name: Multidisciplinary diagnosis and exclusion of other ILD causes
  description: >-
    Integrate symptoms, exposure and medication history, connective-tissue-disease evaluation, HRCT and
    pathology when available. A UIP pattern alone is not sufficient to identify an idiopathic cause.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures,
      connective tissue disease, and drug toxicity).
    explanation: >-
      Alternative etiologies must be excluded before assigning IPF.
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Thus, the accuracy of diagnosis of IPF increases with clinical, radiologic, and histopathologic
      correlation and can be accomplished with a multidisciplinary discussion among experienced clinical
      experts in the field of ILDs
    explanation: >-
      Multidisciplinary integration supports diagnostic accuracy.
- name: Pulmonary function and oxygenation assessment
  diagnosis_term:
    preferred_term: Pulmonary Function Test
    term:
      id: NCIT:C38081
      label: Pulmonary Function Test
  description: >-
    Assess FVC, diffusion capacity and oxygenation at rest and exertion to characterize impairment and
    follow progression. These measurements do not identify the etiology of fibrosis by themselves.
    FVC and DLCO, each expressed as a percentage of predicted, are the two physiologic variables of
    the GAP index, the staging system that assigns IPF to stages I to III by predicted mortality, and
    a baseline DLCO near 40 percent predicted is the threshold the 2011 ATS/ERS/JRS/ALAT statement
    associates with increased mortality risk.
  measurements:
  - preferred_term: FVC percent predicted
    term:
      id: LOINC:19872-1
      label: FVC measured/predicted
  - preferred_term: DLCO percent predicted
    term:
      id: LOINC:98130-8
      label: Diffusion capacity.carbon monoxide/Predicted
  reference_ranges:
  - loinc_term:
      id: LOINC:98130-8
      label: Diffusion capacity.carbon monoxide/Predicted
    unit: '%'
    population: ATS/ERS/JRS/ALAT 2011 statement, baseline measurement in IPF
    notes: >-
      The statement words the threshold as "approximately 40 percent predicted", so the band
      boundary is the statement's approximate figure, not a sharp cut-off it defines; it also
      specifies the measurement as single-breath and hemoglobin-corrected, while the code bound
      is the method-less percent-predicted DLCO. The same statement says baseline FVC is of
      unclear predictive value and that declines in FVC of 5-10 percent over 6 or 12 months may
      predict mortality; a change-over-time criterion is not a level band and is not recorded
      here.
    evidence:
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Diffusing capacity for carbon monoxide (DlCO, single breath, hemoglobin corrected) is more reliably predictive of survival at baseline, and a threshold of approximately 40 percent predicted has been associated with an increased risk of mortality"
      explanation: States the baseline DLCO threshold reproduced as the band boundary below, and its approximate character.
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Baseline FVC is of unclear predictive value"
      explanation: Why no baseline FVC band is recorded on this row from the same statement.
    interpretation_bands:
    - name: Below approximately 40 percent predicted
      upper_bound: 40.0
      unit: '%'
      abnormal_flag: LOW
      interpretation: >-
        Baseline DLCO below the statement's approximate threshold; associated with an increased
        risk of mortality in IPF.
    - name: At or above approximately 40 percent predicted
      lower_bound: 40.0
      unit: '%'
      abnormal_flag: LOW
      interpretation: >-
        Above the mortality-risk threshold. Still flagged LOW because DLCO in IPF is typically
        reduced; this band carries no claim that the value is within a population reference
        interval, which this row deliberately does not record.
  notes: >-
    Identity is bound at the method-less percent-predicted codes, LOINC:19872-1 for FVC and
    LOINC:98130-8 for DLCO, because the GAP index and the pivotal trials express both as a
    fraction of predicted; the absolute-volume FVC code (LOINC:19870-5) sits on the Forced Vital
    Capacity biochemical marker. No GAP bands are recorded: the GAP derivation paper
    (PMID:22586007) is cached as abstract only, and its abstract names FVC and DLCO as the two
    physiology variables and reports stage I to III mortality without stating the FVC or DLCO
    point thresholds. They can be added when a cached record of the paper carries them in
    quotable text.
  evidence:
  - reference: PMID:22586007
    reference_title: "A multidimensional index and staging system for idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Four variables were included in the final model: gender (G), age (A), and 2 lung physiology variables (P) (FVC and Dlco)."
    explanation: The GAP derivation names FVC and DLCO as the two physiologic variables of the IPF staging system, which is why both are bound as measurements on this row.
  - reference: PMID:22586007
    reference_title: "A multidimensional index and staging system for idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Three stages (stages I, II, and III) were identified based on the GAP index with 1-year mortality of 6%, 16%, and 39%, respectively."
    explanation: The staging these two measurements feed; recorded as the row's staging claim, with the point thresholds left unbanded because the abstract does not state them.
  - reference: PMID:24836310
    reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary end point was the annual rate of decline in forced vital capacity (FVC).
    explanation: >-
      The pivotal IPF nintedanib trials used annual FVC decline as the primary physiologic endpoint.
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommendation for long-term oxygen therapy in patients with IPF and clinically significant
      resting hypoxemia is strong
    explanation: >-
      The guideline recognizes clinically significant hypoxemia and its treatment.
- name: Genetic and telomere evaluation in at-risk patients
  description: >-
    Family history, young onset, premature graying, cytopenias or liver disease can suggest inherited
    fibrosis or a telomere biology disorder. Consider specialist genetic evaluation and telomere testing
    in the appropriate context; blood telomere length is not a direct AT2 senescence measurement or a
    stand-alone IPF diagnosis.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/
    reference_title: Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Telomere length measurement should be offered to individuals with pulmonary fibrosis and extrapulmonary
      manifestations of a short telomere syndrome
    explanation: >-
      The chapter recommends targeted telomere assessment in patients with syndromic clues; this does
      not require universal testing or establish IPF solely from a short result.
treatments:
- name: Pirfenidone
  description: >-
    Oral antifibrotic therapy that slows clinical progression and FVC decline. It is not established to
    reverse existing scarring. Gastrointestinal and skin adverse effects and liver monitoring affect use.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: pirfenidone
      term:
        id: CHEBI:32016
        label: pirfenidone
  evidence:
  - reference: PMID:24836312
    reference_title: "A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function,
      exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis.
    explanation: The ASCEND phase 3 trial shows pirfenidone slows clinical progression in IPF.
  target_mechanisms:
  - target: Fibroblast activation and myofibroblast differentiation
    treatment_effect: INHIBITS
    description: >-
      Attenuates TGF-beta-stimulated fibroblast activation in culture; clinical slowing of progression
      is independently supported by ASCEND.
    evidence:
    - reference: PMID:24613900
      reference_title: Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Pirfenidone reduced fibroblast proliferation and attenuated TGF-β-induced α-smooth muscle actin
        (SMA) and pro-collagen (Col)-I mRNA and protein levels.
      explanation: >-
        Primary human lung fibroblast experiments support an antifibrotic cellular effect; the direct
        molecular target and mediation of human benefit are not established.
- name: Nintedanib
  description: Antifibrotic tyrosine kinase inhibitor that slows the rate of forced vital capacity decline in IPF.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: nintedanib
      term:
        id: CHEBI:85164
        label: nintedanib
  evidence:
  - reference: PMID:24836310
    reference_title: "Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is
      consistent with a slowing of disease progression
    explanation: The INPULSIS phase 3 trials show nintedanib slows lung function decline in IPF.
  target_mechanisms:
  - target: Fibroblast activation and myofibroblast differentiation
    treatment_effect: INHIBITS
    description: >-
      Inhibits multiple receptor tyrosine kinases and fibroblast responses; slowing FVC decline does not
      isolate a single causal kinase pathway.
    evidence:
    - reference: PMID:25745043
      reference_title: Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis
        such as fibroblast proliferation, migration and differentiation, and the secretion of ECM.
      explanation: >-
        The pharmacology review summarizes cellular mechanism evidence separately from randomized clinical
        efficacy.
- name: Dasatinib and Quercetin (Senolytic Combination)
  description: >-
    Investigational senolytic combination. An uncontrolled 14-participant study suggested physical-function
    changes without improved pulmonary function. A 12-participant randomized pilot demonstrated feasibility,
    with more nonserious adverse events on D+Q and no meaningful between-group functional difference.
    Neither study establishes antifibrotic efficacy or IPF-lung senescent-cell target engagement.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dasatinib
      term:
        id: CHEBI:49375
        label: dasatinib (anhydrous)
    - preferred_term: quercetin
      term:
        id: CHEBI:16243
        label: quercetin
  evidence:
  - reference: PMID:36857968
    reference_title: 'Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Frailty, pulmonary, or physical function were explored before and after intermittent D + Q; though
      under-powered to evaluate change, these measures do not appear to differ meaningfully between groups.
    explanation: >-
      The randomized pilot supports feasibility, not clinical efficacy.
  - reference: PMID:36857968
    reference_title: 'Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sleep disturbances and anxiety were disproportionately represented in the D + Q arm (4/6 vs 0/6).
    explanation: >-
      Adverse-event imbalance prevents an unqualified tolerability claim.
  - reference: PMID:30616998
    reference_title: 'Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label,
      pilot study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly
      and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty
      index (FI-LAB), and reported health were unchanged.
    explanation: >-
      Source for the uncontrolled 14-participant result described above. The split outcome is the point:
      physical function improved while pulmonary function did not, so an open-label study with no comparator
      supports feasibility and a systemic functional signal, not antifibrotic efficacy or senescent-cell
      target engagement in the IPF lung.
  target_mechanisms:
  - target: Senescent myofibroblast persistence and apoptosis resistance
    treatment_effect: INHIBITS
    description: >-
      Targets senescent fibroblast survival in vitro; efficacy in patients remains investigational.
    evidence:
    - reference: PMID:28230051
      reference_title: Cellular senescence mediates fibrotic pulmonary disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic
        cocktail, dasatinib plus quercetin (DQ), is fibrogenic.
      explanation: >-
        Senolysis and a profibrotic secretome are demonstrated in fibroblasts; human IPF-lung target engagement
        remains unproven.
- name: Nerandomilast
  description: >-
    Oral preferential PDE4B inhibitor approved for adult IPF. The phase III FIBRONEER-IPF trial showed
    less FVC decline at 52 weeks, with most participants receiving background nintedanib or pirfenidone.
    Diarrhea was common. Longer follow-up did not establish a reduction in the composite of acute exacerbation,
    respiratory hospitalization or death, so survival benefit is not asserted.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Nerandomilast
      term:
        id: NCIT:C203229
        label: Nerandomilast
  evidence:
  - reference: PMID:40387033
    reference_title: Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with idiopathic pulmonary fibrosis, treatment with nerandomilast resulted in a smaller
      decline in the FVC than placebo over a period of 52 weeks.
    explanation: >-
      FIBRONEER-IPF randomized 1177 participants, most on background antifibrotics; the endpoint supports
      slowing decline rather than reversal.
  - reference: PMID:41738262
    reference_title: 'Nerandomilast in idiopathic pulmonary fibrosis: data from the whole follow-up period of the FIBRONEER-IPF trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nerandomilast had no effect on the composite endpoint of time to first acute exacerbation of IPF,
      hospitalization for respiratory cause, or death
    explanation: >-
      The final follow-up did not show benefit on this composite clinical endpoint.
  target_mechanisms:
  - target: Fibroblast activation and myofibroblast differentiation
    treatment_effect: INHIBITS
    description: >-
      Preferential PDE4B inhibition suppresses myofibroblast transformation and proliferation in primary
      IPF fibroblast cultures.
    evidence:
    - reference: PMID:35517783
      reference_title: BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        BI 1015550 inhibited transforming growth factor-β-stimulated myofibroblast transformation and
        the mRNA expression of various extracellular matrix proteins, as well as basic fibroblast growth
        factor plus interleukin-1β-induced cell proliferation.
      explanation: >-
        Primary IPF fibroblast experiments support antiproliferative and differentiation effects; the
        2023 corrigendum corrects Table 1 sample sizes without changing this conclusion.
- name: Supplemental oxygen
  description: >-
    Corrects clinically significant hypoxemia without reversing fibrosis.
  treatment_term:
    preferred_term: Oxygen Therapy
    term:
      id: NCIT:C94624
      label: Oxygen Therapy
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommendation for long-term oxygen therapy in patients with IPF and clinically significant
      resting hypoxemia is strong
    explanation: >-
      The guideline supports this intervention in the indicated clinical setting.
  target_mechanisms:
  - target: Hypoxemia
    treatment_effect: MODULATES
    description: >-
      Corrects clinically significant hypoxemia without reversing fibrosis.
    evidence:
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The recommendation for long-term oxygen therapy in patients with IPF and clinically significant
        resting hypoxemia is strong
      explanation: >-
        The guideline supports this intervention in the indicated clinical setting.
- name: Pulmonary rehabilitation
  description: >-
    Exercise and supportive rehabilitation can improve functional capacity and symptoms.
  treatment_term:
    preferred_term: Pulmonary Rehabilitation
    term:
      id: NCIT:C157966
      label: Pulmonary Rehabilitation
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommendation for pulmonary rehabilitation in patients with IPF is weak
    explanation: >-
      The guideline supports this intervention in the indicated clinical setting.
  target_mechanisms:
  - target: Exercise intolerance
    treatment_effect: MODULATES
    description: >-
      Exercise and supportive rehabilitation can improve functional capacity and symptoms.
    evidence:
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The recommendation for pulmonary rehabilitation in patients with IPF is weak
      explanation: >-
        The guideline supports this intervention in the indicated clinical setting.
- name: Lung transplantation
  description: >-
    Consider transplantation for eligible patients with progressive disease. Telomere-related marrow,
    immune and liver complications influence assessment and immunosuppression.
  treatment_term:
    preferred_term: Lung Transplantation
    term:
      id: NCIT:C15274
      label: Lung Transplantation
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommendation for lung transplantation in appropriate patients with IPF is strong (⊕○○○).
    explanation: >-
      The guideline supports this intervention in the indicated clinical setting.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/
    reference_title: Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Adjustment of immunosuppressive medication may be required to avoid drug toxicities in those w/hematologic
      abnormalities.
    explanation: >-
      Management guidance identifies a telomere-related transplant toxicity consideration rather than
      a blanket contraindication.
  target_mechanisms:
  - target: Architectural distortion and gas-exchange failure
    treatment_effect: MODULATES
    description: >-
      Consider transplantation for eligible patients with progressive disease. Telomere-related marrow,
      immune and liver complications influence assessment and immunosuppression.
    evidence:
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The recommendation for lung transplantation in appropriate patients with IPF is strong (⊕○○○).
      explanation: >-
        The guideline supports this intervention in the indicated clinical setting.
- name: Avoid prednisone-azathioprine-N-acetylcysteine combination
  description: >-
    This chronic three-drug regimen should not be used to treat IPF. PANTHER-IPF found excess deaths and
    hospitalizations without physiological or clinical benefit. This result is specific to the regimen
    and does not establish that immune cells have no mechanistic role or address every acute-exacerbation
    treatment question.
  evidence:
  - reference: PMID:22607134
    reference_title: Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary
      fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with
      placebo.
    explanation: >-
      The randomized PANTHER-IPF result supports avoiding this regimen.
- name: Genetic counseling for inherited fibrosis
  description: >-
    Offer specialist counseling when inherited pulmonary fibrosis is suspected or a pathogenic variant
    is identified. Discuss variable penetrance, possible anticipation and telomere inheritance, family
    evaluation and the distinction between variant transmission and disease prediction.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/
    reference_title: Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with a ... associated with predisposition to pulmonary fibrosis has
      a 50% chance of inheriting the pathogenic variant.
    explanation: >-
      The recurrence statement applies to autosomal dominant monogenic predisposition, not every sporadic
      IPF case; inheritance of a variant does not predict age of onset or guarantee disease.
mechanistic_hypotheses:
- hypothesis_group_id: injury_centric_model
  hypothesis_label: Injury-Centric Wound Healing Model
  status: CANONICAL
  description: >-
    Repetitive alveolar epithelial injury is modeled as the primary upstream driver; AT2 cell senescence
    and subsequent fibroblast activation are downstream consequences of failed wound healing. Fibrosis
    represents an aberrant, non-resolving repair response to injury in genetically or environmentally
    susceptible individuals.
  evidence:
  - reference: PMID:35563849
    reference_title: "Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it has been suggested that repeated microinjuries of epithelial cells induce a wound healing response,
      during which fibroblasts differentiate into myofibroblasts.
    explanation: >-
      Supports the injury-centric model in which repetitive microinjury is the upstream initiating event
      that leads to fibroblast activation.
  notes: >-
    Retained as CANONICAL as a useful injury-and-aberrant-repair framework. Susceptibility, persistent
    signaling and regenerative failure can sustain fibrosis after an initiating insult; the framework
    does not require an identified recurrent exposure in every patient.
- hypothesis_group_id: senescence_first_model
  hypothesis_label: Senescence-First (Stem-Cell Exhaustion) Model
  status: ALTERNATIVE
  description: >-
    AT2 senescence and loss of regenerative capacity may be proximal drivers of fibrosis, particularly
    in telomere-associated disease but also after other stress pathways. Human genetics and tissue studies
    support relevance; TRF1 and Sin3a mouse perturbations demonstrate spontaneous fibrosis, whereas other
    telomerase models require injury. Immune-cell-free organoids establish one epithelial-fibroblast route.
    The relative contributions of this route and immune amplification in human disease remain unresolved.
  evidence:
  - reference: PMID:37653024
    reference_title: "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in
      non-inflammatory lung fibrogenesis.
    explanation: >-
      Immune-cell-free organoids support an epithelial-fibroblast route in vitro, without proving whole-animal
      immune independence.
  - reference: PMID:33808277
    reference_title: "Telomeres in Interstitial Lung Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Loss of regenerative potential of alveolar type II epithelial cells (AT2) cells following injury
      has been postulated to underlie telomeropathy-associated lung fibrosis, with concomitant excessive
      proliferation of airway cells displaying abnormal phenotypes
    explanation: >-
      Review describes telomere-driven loss of AT2 regenerative capacity as a mechanistic explanation
      for the strong age and telomere-length associations in IPF.
  - reference: PMID:33197388
    reference_title: "Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that
      shorter telomeres cause IPF
    explanation: >-
      Published Mendelian randomization supports a contribution of shorter telomeres to IPF susceptibility
      under instrumental-variable assumptions. The COPD comparator does not establish disease specificity
      across all conditions or AT2-specific causal timing.
  - reference: PMID:31000627
    reference_title: "Telomerase reverse transcriptase ameliorates lung fibrosis by protecting alveolar epithelial cells against senescence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      SPC-Tert cKO mice did not develop pulmonary fibrosis spontaneously up to 9 months of TERT deficiency.
      However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis
      compared with control mice
    explanation: >-
      AT2-specific TERT loss increases injury susceptibility and senescence without a significant change
      in AT2 telomere length. The absence of spontaneous fibrosis applies to this model only.
  - reference: PMID:41728098
    reference_title: "Shortened Telomere Length as a Risk Factor for Idiopathic Pulmonary Fibrosis: A Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pooled analysis showed shorter telomere length in IPF patients compared to controls (SMD: -0.84,
      95%CI -1.21 to -0.48, Z = 4.55, p < 0.00001)
    explanation: >-
      Observational pooled measurements support shorter telomeres in IPF. They complement genetic evidence
      but cannot alone establish causal ordering or an exclusive senescence-first subtype.
  - reference: PMID:34524912
    reference_title: "A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: a potential drug target in IPF."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cGAS expression in fibrotic tissue from lungs of patients with IPF was detected within cells immunoreactive
      for epithelial cell adhesion molecule (EpCAM) and p21, epithelial and senescence markers, respectively
    explanation: >-
      Human colocalization supports pathway presence, while cultured-cell perturbations support cGAS-dependent
      senescence amplification. This does not establish universal STING activation or recruited immune-cell
      necessity.
  - reference: PMID:31922885
    reference_title: "Diverse Injury Pathways Induce Alveolar Epithelial Cell CCL2/12, Which Promotes Lung Fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice with lung epithelial cell-specific deletion of CCL12 were protected from bleomycin-induced
      fibrosis
    explanation: >-
      Epithelial CCL12 deletion limits macrophage recruitment and fibrosis in a specific bleomycin paradigm.
      Global deletion was not protective, and this is not a refutation of all epithelial-autonomous routes.
  - reference: PMID:27699234
    reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing
      cells, leads to age-dependent lung remodeling and fibrosis.
    explanation: >-
      Conditional TRF1 deletion causes spontaneous fibrosis after prolonged epithelial telomere dysfunction;
      this severe uncapping model is distinct from ordinary age-related shortening.
  - reference: PMID:32991815
    reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent
      cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis.
    explanation: >-
      An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin;
      it does not establish immune independence or the initiating lesion in all human IPF.
  notes: >-
    Retain ALTERNATIVE as a hypothesis about causal ordering, without assigning a validated exclusive
    patient subtype. OpenScientist provides useful multi-trigger and multi-cellular leads, but its universal
    second-hit and obligate-immune claims are rejected. Short leukocyte telomere frequencies do not define
    the fraction of IPF mediated by AT2 senescence. TERT deletion, telomere shortening and shelterin uncapping
    are distinct perturbations. The assessment records corrected source interpretation and missing declared
    artifacts.
- hypothesis_group_id: feedback_loop_convergence_model
  hypothesis_label: Convergent Self-Sustaining Feedback Loop Model
  status: ALTERNATIVE
  description: >-
    Epithelial stress, senescence, fibroblast persistence and matrix-derived mechanical signals may reinforce
    one another after initiation. Experimental TGF-beta and matrix-stiffness feedback support this convergent
    framework, but their relative necessity and therapeutic importance in human IPF remain unresolved.
  evidence:
  - reference: PMID:34813355
    reference_title: "Pathogenic Mechanisms Underlying Idiopathic Pulmonary Fibrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types
      and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context
      of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic),
      leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated
      epithelial repair.
    explanation: >-
      Annual Review of Pathology review frames IPF as a convergence of multiple predisposing factors and
      cell types, consistent with the feedback loop model in which no single upstream event fully explains
      the disease.
  notes: >-
    This synthesis complements upstream injury and senescence hypotheses. Response to an antifibrotic
    drug does not by itself identify the initiating lesion or establish which feedback loop mediated benefit.
discussions:
- discussion_id: disc_ipf_injury_vs_senescence_ordering
  prompt: >-
    Is repetitive alveolar epithelial injury the primary upstream driver of IPF, or does age-related AT2
    cell senescence and telomere attrition precede and predispose to fibrosis independently of ongoing
    injury?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#AT2 cell senescence and SASP
  rationale: >-
    Human disease likely combines epithelial susceptibility, injury and failed repair. TRF1 and Sin3a
    perturbations demonstrate spontaneous fibrosis in mice, while AT2-specific TERT loss and certain surfactant
    variants require additional injury. The unresolved question is how these distinct model-specific mechanisms
    map onto human causal ordering, not whether any spontaneous model exists.
  evidence:
  - reference: PMID:27699234
    reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results demonstrate that prolonged telomere dysfunction in type II AECs, but not collagen-expressing
      cells, leads to age-dependent lung remodeling and fibrosis.
    explanation: >-
      Conditional TRF1 deletion causes spontaneous fibrosis after prolonged epithelial telomere dysfunction;
      this severe uncapping model is distinct from ordinary age-related shortening.
  - reference: PMID:32991815
    reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent
      cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis.
    explanation: >-
      An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin;
      it does not establish immune independence or the initiating lesion in all human IPF.
- discussion_id: disc_ipf_ecm_feedback_irreversibility
  prompt: >-
    Which epithelial, mesenchymal and matrix-derived feedback processes sustain progressive IPF, how necessary
    are they in different patients, and which combinations are therapeutically tractable?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Excessive extracellular matrix deposition
  - pathophysiology#Aberrant basaloid cell emergence
  rationale: >-
    Autocrine TGF-beta, matrix mechanics and persistent mesenchymal states can sustain experimental fibrosis.
    Human relative contributions and optimal combinations of interventions remain unresolved. Antifibrotic
    therapies slow FVC decline but do not establish reversal, while senolytic clinical studies remain
    small feasibility trials.
- discussion_id: disc_ipf_gut_lung_axis_causality
  prompt: >-
    Does gut dysbiosis drive IPF progression (dysbiosis → fibrosis), or is it a secondary consequence
    of systemic inflammation and drug effects in established IPF (fibrosis → dysbiosis)? Are microbial
    metabolite deficits (SCFA, secondary bile acids) individually sufficient to amplify pulmonary fibrosis,
    or do they require cofactors? Can fecal microbiota transplantation attenuate pulmonary inflammation
    in human ILD?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Gut dysbiosis and microbial metabolite dysregulation
  rationale: >-
    The reviewed evidence combines clinical associations and preclinical gut-lung experiments. Directionality,
    specific microbial mediators, and independence from disease severity, diet and drug exposure remain
    unresolved. Human microbiome-directed therapeutic benefit is not established by the cited review.
  proposed_experiments:
  - experiment_id: exp_ipf_microbiome_temporal_cohort
    name: Longitudinal microbiome profiling in IPF cohorts
    description: >-
      Use longitudinal microbiome profiling with matched lung-function measures, diet, medication and
      severity covariates to assess temporal association. Temporal precedence alone does not establish
      causality.
  - experiment_id: exp_ipf_germ_free_bleomycin
    name: Germ-free and antibiotic-depleted mouse IPF models
    description: >-
      Germ-free or antibiotic-depleted mouse bleomycin models to test whether microbiota depletion attenuates
      pulmonary fibrosis, establishing a causal contribution of gut microbiota to lung fibrotic pathways.
  - experiment_id: exp_ipf_scfa_supplementation
    name: SCFA supplementation in IPF mouse models
    description: >-
      SCFA (butyrate and propionate) supplementation in bleomycin-induced pulmonary fibrosis mouse models
      to determine whether restoring microbial metabolite levels reduces fibrotic burden and pro-inflammatory
      cytokines.
- discussion_id: disc_ipf_muc5b_senescence_interaction
  prompt: >-
    Does MUC5B overexpression promote, protect against, or act independently of alveolar type II cell
    senescence? The two best-supported susceptibility mechanisms for sporadic IPF are expressed in the
    same epithelial cells but have not been studied in combination.
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#MUC5B
  - pathophysiology#Distal MUC5B overexpression and impaired clearance
  - pathophysiology#AT2 cell senescence and SASP
  rationale: >-
    The rs35705950 promoter variant is the strongest common genetic risk factor for sporadic IPF, and
    Hancock et al. report MUC5B co-expression with surfactant protein C in type 2 alveolar epithelium
    and in honeycomb-cyst epithelium (PMID:30560893), which places it in the same cells this entry models
    as senescent. The mechanism it is curated under, impaired distal mucociliary clearance, is not a senescence
    mechanism, and no study has asked whether MUC5B overexpression induces, protects against, or is orthogonal
    to AT2 senescence. If the two mechanisms are independent, risk should be close to additive and the
    mucociliary and senescence routes would describe partly different patients; if they interact, departure
    from additivity is expected. An OpenScientist report of the senescence-first model records PubMed
    searches for MUC5B with senescence and with telomere that returned no relevant studies, but commits
    no query log, so this is a reported absence rather than a documented one.
  proposed_experiments:
  - experiment_id: exp_ipf_muc5b_senescence_coexpression
    name: Co-expression of MUC5B and senescence markers in IPF tissue
    description: >-
      Quantify MUC5B alongside p16, p21 and senescence-associated beta-galactosidase in the same alveolar
      and honeycomb-cyst epithelial cells in IPF lung sections, stratified by rs35705950 genotype, to
      establish whether the mucin-high and senescent epithelial compartments are the same population
      or distinct ones.
    would_support:
    - pathophysiology#AT2 cell senescence and SASP
    supporting_outcome:
    - >-
        MUC5B-high alveolar epithelial cells are enriched for senescence markers relative to MUC5B-low
        cells from the same lungs, indicating that the mucociliary susceptibility route feeds the senescence
        node rather than bypassing it.
    refuting_outcome:
    - >-
        MUC5B-high and senescence-marker-high epithelial cells occupy separate, non-overlapping compartments,
        which would be consistent with two routes to fibrosis acting in different cells or different patients.
  - experiment_id: exp_ipf_muc5b_telomere_epistasis
    name: MUC5B genotype by telomere length interaction in an IPF cohort
    description: >-
      In an IPF cohort powered for an interaction term, genotype rs35705950, measure leukocyte telomere
      length, and fit additive and multiplicative interaction models for FVC decline and transplant-free
      survival. Leukocyte telomere length is an imperfect proxy for alveolar epithelial senescence, so
      a null interaction would not by itself exclude convergence in the lung.
classifications:
  nih_research_priority:
  - classification_value: NIH_HT_89_cellular_quiescence_senescence_cell_death_in
    notes: Pathophysiology conforms to the telomere attrition module(s) — hallmark-of-aging mechanism(s) — making this entry a relevant model for NIH Highlighted Topic 89 (cellular quiescence, senescence, and cell death in aging and disease).
datasets:
# EBI Single Cell Expression Atlas re-analysis of the Tsukui et al. collagen-producing lung cell atlas
- accession: scea:E-CURD-126
  title: Single-cell RNA-sequencing of normal and fibrotic human lungs (collagen-producing lung cell atlas)
  description: >-
    EBI Single Cell Expression Atlas harmonized re-analysis (102,932 cells) of the Tsukui et al. collagen-producing
    lung cell atlas, restricted to the human lung subset (normal, idiopathic pulmonary fibrosis, and scleroderma).
    Resolves collagen-producing mesenchymal heterogeneity and identifies CTHRC1-expressing fibroblasts
    that appear uniquely in fibrotic lungs and concentrate within fibroblastic foci — cell-resolution
    support for the activated-mesenchymal-cell and excessive-ECM steps of the fibrotic_response module
    to which this entry conforms.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_types:
  - preferred_term: fibrotic and normal lung tissue
    tissue_term:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  conditions:
  - idiopathic pulmonary fibrosis
  - systemic sclerosis (scleroderma) lung
  - normal lung
  platform: droplet single-cell RNA-seq (10x Genomics)
  publication: PMID:32317643
  evidence:
  - reference: PMID:32317643
    reference_title: "Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs."
    explanation: >-
      Human scRNA-seq (the subset harmonized as SCEA E-CURD-126) shows CTHRC1-expressing fibroblasts arising
      specifically in fibrotic lungs, giving cell-resolution support for the pathogenic mesenchymal-cell
      / excessive-ECM nodes of the fibrotic_response module.
  notes: >-
    Aggregator provenance: the harmonized re-analysis is hosted by the EBI Single Cell Expression Atlas
    (accession E-CURD-126); the underlying study is Tsukui et al., Nat Commun 2020 (PMID:32317643, DOI:10.1038/s41467-020-15647-5).
    The original study is a mixed murine + human atlas; only the human lung subset is cited here (evidence_source
    HUMAN_CLINICAL).
- accession: geo:GSE262882
  title: Activation of Fibroblast LRP1 by AT2-secreted MDK Affects OTUB1/SLC7A11 Ubiquitination to Inhibit Fibroblast Ferroptosis in Idiopathic Pulmonary Fibrosis.
  description: Idiopathic pulmonary fibrosis (IPF), a chronic interstitial fibrosing pneumonia of unknown cause, is characterized by an irreversible decrease in alveolar cells and an increase in fibroblasts. In our research, the numbers of AT2 cells and fibroblasts are abnormally regulated, but AT1 cells are significantly reduced in lung tissue sections from patients with IPF and mice. By analyzing the single-cell sequence from GEO database and experimental validation both in vivo and in vitro, it is found that the abnormally regulated AT2 cells secreting a large amount of MDK to activate the CTHRC1+ fibroblasts LRP1 receptor and inhibit the ferroptosis of fibroblasts.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 6
  publication: PMID:42305620
  notes: Identified by GEO DataSets index search for Idiopathic Pulmonary Fibrosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE314583
  title: Toll-Like-Receptor 5 Reduces Lung Dysbiosis and Protects Against Pulmonary Fibrosis
  description: Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation. IPF results from maladaptive responses to lung epithelial injury, but the underlying mechanisms remain unclear. Here, we show that deficiency in the innate immune receptor, toll-like receptor 5 (TLR5), is associated with IPF in humans and with increased susceptibility to experimental fibrosis in mice, while activation of lung epithelial TLR5 through a synthetic flagellin analog protects from experimental fibrosis. Mechanistically, epithelial TLR5 activation induces antimicrobial gene expression and ameliorates dysbiosis after lung injury.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  sample_count: 106
  publication: PMID:42234773
  notes: Identified by GEO DataSets index search for Idiopathic Pulmonary Fibrosis (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001004758
  title: The transition from normal lung anatomy to minimal and established fibrosis in Idiopathic Pulmonary Fibrosis
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Idiopathic Pulmonary Fibrosis"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001005794
  title: Profibrotic priming of airway cell types in idiopathic pulmonary fibrosis and drug inhibition in single-cell resolution
  description: The cause and etiology of idiopathic pulmonary fibrosis, a severe chronic lung disorder with limited treatment options, is still poorly understood. Early genetic studies hinted that airway epithelial cells play an important role in the development of IPF while more recent single-cell RNA sequencing atlases from explant IPF lungs have focused on macrophages. In this study, we used air-liquid interface cultures of primary cells taken from the subsegmental bronchi of IPF patients, reflecting early-stage fibrosis, to interrogate the single-cell transcriptional landscape of the airway mucosa. We identified IPF-enriched cell-cell interaction pathways.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Idiopathic Pulmonary Fibrosis"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: massive:MSV000093453
  title: O-GlcNAc Containing Proteins in Normal and Idiopathic Pulmonary Fibrosis Human Fibroblasts
  description: 'Isolated normal and IPF fibroblasts were homogenized in cold MilliQ water using a bullet blender. Samples were centrifuged and inhibitors were added: HALT (Thermo Fisher Scientific), Z-Pugnac (Tocris), Thiamet G (Cayman Chemicals), and benzonase (E1014, Millipore, Sigma). O-GlcNAc enzymatic labeling and protein capturing was performed as described using a Click-IT enrichment kit following the manufacturer''s protocol (cat no: C33368, C33372, and C10416; Thermo Fisher Scientific).'
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Idiopathic Pulmonary Fibrosis"). Retrieved 2026-08-02.
- accession: massive:MSV000098032
  title: Markers of neutrophil degranulation in the lung microenvironment linked to idiopathic pulmonary fibrosis severity and survival
  description: Idiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying circulating prognostic markers. Using a proteomic discovery method followed by ELISA confirmation in multiple cohorts we explored novel markers of IPF survival in bronchoalveolar lavage fluid (BALF)
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Idiopathic Pulmonary Fibrosis"). Retrieved 2026-08-02.
- accession: massive:MSV000094806
  title: Proteomic profiling of bronchoalveolar lavage fluid uncovers unique protein clusters linked to survival in idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features
  description: This study aimed to delineate molecular phenotypes of the lung microenvironment across idiopathic interestitial pneumonias, namely interstitial pneumonia with autoimmune features (IPAF)and idiopathic pulmonary fibrosis (IPF) through proteomic analysis of bronchoalveolar lavage fluid (BALF).
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Idiopathic Pulmonary Fibrosis"). Retrieved 2026-08-02.

experimental_models:
- name: Microengineered alveolar array lung-on-chip with breathing mechanics
  description: >-
    An array of geometrically defined alveolar units suspended on a thin collagen-elastin hydrogel membrane
    engineered to match the dimensions and mechanical fragility of the native alveolar basement membrane,
    with human alveolar epithelial cells and lung fibroblasts co-cultured across it and subjected to controlled
    cyclic deflection emulating breathing. Precision injection moulding and an SBS microwell format make
    it medium-throughput, which is what allows drug testing rather than single-device demonstration.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  cell_types:
  - preferred_term: Pulmonary alveolar epithelial cell
    term:
      id: CL:0000322
      label: pulmonary alveolar epithelial cell
  - preferred_term: Lung fibroblast
    term:
      id: CL:0002553
      label: fibroblast of lung
  conditions:
  - cyclic mechanical stretch (breathing-mimetic)
  - static control
  - TGF-beta 1 stimulation
  - nintedanib treatment
  culture_system: Injection-moulded alveolar array chip with suspended collagen-elastin hydrogel membrane and cyclic actuation
  publication: PMID:41406599
  modeled_mechanisms:
  - target: Fibroblast activation and myofibroblast differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cyclic stretch applied together with TGF-beta 1 amplified fibrotic signalling well beyond TGF-beta
      1 alone. This makes breathing motion an explicit cofactor of fibroblast activation rather than background,
      which is the mechanistic claim a static culture cannot test.
    limitations: >-
      Amplification was demonstrated with exogenous TGF-beta 1 rather than with the endogenous injury
      signals of IPF, and the co-culture uses non-diseased alveolar epithelial cells and fibroblasts,
      so it models the mechanical contribution to fibrotic signalling rather than IPF-specific fibroblast
      biology such as the aberrant basaloid state.
    readouts:
    - name: Extracellular matrix gene expression under cyclic stretch with TGF-beta 1
      target: Fibroblast activation and myofibroblast differentiation
      direction: INCREASED
      interpretation: >-
        Collagen I, collagen III, and fibronectin induction is the activation readout, and its stretch-dependence
        is the finding.
      evidence:
      - reference: PMID:41406599
        reference_title: Microengineered alveolar array lung-on-chip with hydrogel membrane and simulated breathing mechanics for anti-fibrotic testing.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: We demonstrate that cyclic stretching significantly amplifies fibrotic signaling in the presence of transforming growth factor-beta 1 (TGF-β1), evidenced by increased expression of extracellular matrix (ECM) components such as collagen I, collagen III, and fibronectin.
        explanation: Reports the matrix-gene induction and its dependence on cyclic stretch.
    evidence:
    - reference: PMID:41406599
      reference_title: Microengineered alveolar array lung-on-chip with hydrogel membrane and simulated breathing mechanics for anti-fibrotic testing.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Human alveolar epithelial cells and lung fibroblasts are co-cultured on a membrane and subjected to cyclic biomechanical stress that mimics respiratory movements.
      explanation: Establishes the epithelial-fibroblast co-culture under breathing mechanics as the model configuration relevant to this node.
  - target: Excessive extracellular matrix deposition
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Matrix protein and PAI-1 expression rose under profibrotic stimulation and fell with nintedanib,
      an approved IPF antifibrotic, giving the model pharmacological validation against the standard of
      care for this node.
    limitations: >-
      Readouts are expression-level over days rather than accumulated cross-linked matrix, and nintedanib
      reversal establishes assay responsiveness rather than predictive value for novel compounds. The
      membrane is a defined collagen-elastin hydrogel, not fibrotic human lung matrix, so matrix-stiffness
      feedback is not reproduced.
    readouts:
    - name: ECM protein and PAI-1 expression under nintedanib
      target: Excessive extracellular matrix deposition
      direction: DECREASED
      interpretation: >-
        Reduction by an approved antifibrotic confirms the readout responds in the therapeutically expected
        direction.
      evidence:
      - reference: PMID:41406599
        reference_title: Microengineered alveolar array lung-on-chip with hydrogel membrane and simulated breathing mechanics for anti-fibrotic testing.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Treatment with the anti-fibrotic drug nintedanib reduced expression of ECM proteins and plasminogen activator inhibitor-1 (PAI-1), validating the system's utility for pharmacological testing.
        explanation: Directly reports the drug-responsive matrix readout.
    evidence:
    - reference: PMID:41406599
      reference_title: Microengineered alveolar array lung-on-chip with hydrogel membrane and simulated breathing mechanics for anti-fibrotic testing.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Treatment with the anti-fibrotic drug nintedanib reduced expression of ECM proteins and plasminogen activator inhibitor-1 (PAI-1), validating the system's utility for pharmacological testing.
      explanation: Supports a drug-responsive expression surrogate for matrix deposition, without directly measuring accumulated cross-linked scar.
- name: Immune-cell-free AT2-lineage and fibroblast organoids
  experimental_model_type: ORGANOID
  description: >-
    Mouse and human lung-derived organoid co-cultures exposed to bleomycin isolate direct epithelial-fibroblast
    signaling. The assay tests an immune-cell-free route under defined conditions.
  cell_source: Mouse and human lung-derived epithelial cells and fibroblasts
  publication: PMID:37653024
  evidence:
  - reference: PMID:37653024
    reference_title: Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess
      the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts
      by excluding immune cells.
    explanation: >-
      The co-culture removes immune cells to isolate epithelial-mesenchymal communication.
  modeled_mechanisms:
  - target: AT2 cell senescence and SASP
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Bleomycin-induced DNA damage activates p53 and a profibrotic secretory epithelial state.
    limitations: >-
      Organoids lack the immune, vascular and whole-organ context; experimental sufficiency does not establish
      in-vivo immune independence.
    evidence:
    - reference: PMID:37653024
      reference_title: "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1
        transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related
        factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation.
        Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular
        system in non-inflammatory lung fibrogenesis.
      explanation: >-
        The immune-cell-free organoid experiment establishes epithelial-fibroblast sufficiency under bleomycin
        stimulation; accompanying mouse genetics do not imply immune independence of whole-animal disease.
    readouts:
    - name: p53-associated SASP and myofibroblast induction
      target: AT2 cell senescence and SASP
      direction: INCREASED
      interpretation: >-
        Bleomycin-induced DNA damage activates p53 and a profibrotic secretory epithelial state.
      evidence:
      - reference: PMID:37653024
        reference_title: "Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1
          transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related
          factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation.
          Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular
          system in non-inflammatory lung fibrogenesis.
        explanation: >-
          The immune-cell-free organoid experiment establishes epithelial-fibroblast sufficiency under
          bleomycin
          stimulation; accompanying mouse genetics do not imply immune independence of whole-animal disease.
notes: >-
  The pathograph combines human associations with explicitly identified experimental mechanisms. Neither
  an obligatory exogenous second hit nor universal immune-cell dependence is established. Short leukocyte
  telomere length is an enrichment feature, not a validated boundary excluding senescence mechanisms in
  other patients. The OpenScientist report has an independent claim-level assessment. The full GeneReviews
  Pulmonary Fibrosis Predisposition Overview, revised 2025-12-04, was reviewed across clinical features,
  differential diagnosis, genetic evaluation, management, surveillance and counseling; direct chapter
  evidence is cited through its fetched Bookshelf URL. Its broader familial pulmonary fibrosis scope is
  not equated with IPF.
histopathology:
- name: Usual interstitial pneumonia pattern
  description: >-
    Patchy interstitial fibrosis with temporal and spatial heterogeneity, fibroblast foci and honeycomb
    remodeling, most marked subpleurally and paraseptally. UIP must be interpreted with clinical and radiologic
    findings because it is not specific to IPF.
  finding_term:
    preferred_term: Usual interstitial pneumonia fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  diagnostic: true
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The histopathologic hallmark and chief diagnostic criterion is a heterogeneous appearance at low
      magnification in which areas of fibrosis with scarring and honeycomb change alternate with areas
      of less affected or normal parenchyma
    explanation: >-
      The statement describes the heterogeneous UIP pattern.
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The fibrotic zones are composed mainly of dense collagen, although scattered convex subepithelial
      foci of proliferating fibroblasts and myofibroblasts (so-called fibroblast foci) are a consistent
      finding.
    explanation: >-
      Fibroblast foci connect the morphology to matrix-producing mesenchymal cells.
  notes: >-
    Highly characteristic in the proper diagnostic setting, not pathognomonic in isolation.
differential_diagnoses:
- name: Connective tissue disease-associated ILD
  description: >-
    Can produce fibrotic interstitial lung disease with an overlapping UIP pattern.
  distinguishing_features:
  - >-
    Assess systemic rheumatic manifestations and serology in the clinical context.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The major differential diagnostic considerations include UIP in other clinical settings such as
      connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis),
      and pneumoconioses (especially asbestosis).
    explanation: >-
      The source identifies major alternative causes of a UIP pattern.
- name: Fibrotic hypersensitivity pneumonitis
  description: >-
    Can produce fibrotic interstitial lung disease with an overlapping UIP pattern.
  distinguishing_features:
  - >-
    Assess antigen exposure, air trapping and other clinical, imaging and pathologic evidence.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The major differential diagnostic considerations include UIP in other clinical settings such as
      connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis),
      and pneumoconioses (especially asbestosis).
    explanation: >-
      The source identifies major alternative causes of a UIP pattern.
- name: Asbestosis
  description: >-
    Can produce fibrotic interstitial lung disease with an overlapping UIP pattern.
  distinguishing_features:
  - >-
    Assess occupational asbestos exposure and pleural or other compatible imaging findings.
  evidence:
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The major differential diagnostic considerations include UIP in other clinical settings such as
      connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis),
      and pneumoconioses (especially asbestosis).
    explanation: >-
      The source identifies major alternative causes of a UIP pattern.
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
  title: https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf
  tags:
  - GeneReviews
  findings: []
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/
  title: Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
clinical_trials:
- name: NCT05321069
  phase: PHASE_III
  status: COMPLETED
  description: >-
    FIBRONEER-IPF evaluated two nerandomilast doses versus placebo, including patients on background antifibrotics.
    The published primary endpoint was FVC change at 52 weeks.
  notes: >-
    Registry checked 2026-09-04: 1177 actual participants; completion 2024-12-17. Outcome evidence is
    in the nerandomilast treatment record.
  evidence:
  - reference: clinicaltrials:NCT05321069
    reference_title: A Double Blind, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of BI 1015550 Over at Least 52 Weeks in Patients With Idiopathic Pulmonary Fibrosis (IPF)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If they already take nintedanib or pirfenidone for their IPF, they can continue treatment throughout
      the study.
    explanation: >-
      The registry documents allowed background therapy.
- name: NCT02874989
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Senolytic D+Q pilot program comprising open-label and randomized components, with 26 actual participants
    in the registry. Published components involved 14 open-label and 12 randomized participants.
  notes: >-
    Registry checked 2026-09-04: completion 2019-06-03. The archived official title says open label, while
    the design module also records a randomized participant-masked component. Published efficacy remains
    inconclusive.
  evidence:
  - reference: clinicaltrials:NCT02874989
    reference_title: 'Targeted Removal of Pro-Inflammatory Cells: An Open Label Human Pilot Study in Idiopathic Pulmonary Fibrosis'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study team hypothesizes that intermittent (3 doses administered over 3 consecutive days in 3
      consecutive weeks) oral administration of combination Dasatinib (100 mg/d) + Quercetin (1250 mg/d)
      will be safe and well tolerated in patients with IPF.
    explanation: >-
      Registry text describes the hypothesis and schedule, not a demonstrated safety or efficacy result.
animal_models:
- name: AT2-specific TRF1 conditional deletion
  species: Mus musculus
  genotype: SPC-Cre TRF1fl/fl
  description: >-
    Prolonged AT2 shelterin deletion produces spontaneous senescence-associated remodeling and collagen
    deposition, unlike the collagen-expressing-cell deletion comparator.
  publication: PMID:27699234
  evidence:
  - reference: PMID:27699234
    reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling
      characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells, collagen
      deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial cells.
    explanation: >-
      Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.
  modeled_mechanisms:
  - target: Alveolar epithelial telomere dysfunction
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      TRF1 loss perturbs telomere protection and eventually shortens telomeres.
    limitations: >-
      Severe engineered uncapping and mouse telomere biology differ from ordinary human age-related attrition.
    evidence:
    - reference: PMID:27699234
      reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling
        characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells,
        collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial
        cells.
      explanation: >-
        Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.
    readouts:
    - name: Epithelial senescence and collagen deposition
      target: Alveolar epithelial telomere dysfunction
      direction: INCREASED
      interpretation: >-
        TRF1 loss perturbs telomere protection and eventually shortens telomeres.
      evidence:
      - reference: PMID:27699234
        reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling
          characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells,
          collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial
          cells.
        explanation: >-
          Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.
  - target: Excessive extracellular matrix deposition
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Collagen deposition increases after prolonged epithelial telomere dysfunction.
    limitations: >-
      Spontaneous experimental fibrosis does not establish the initiating lesion or immune independence
      of every human case.
    evidence:
    - reference: PMID:27699234
      reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling
        characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells,
        collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial
        cells.
      explanation: >-
        Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.
    readouts:
    - name: Lung collagen deposition
      target: Excessive extracellular matrix deposition
      direction: INCREASED
      interpretation: >-
        Collagen deposition increases after prolonged epithelial telomere dysfunction.
      evidence:
      - reference: PMID:27699234
        reference_title: Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Deletion of TRF1 in type II AECs for up to 9 months resulted in short telomeres and lung remodeling
          characterized by increased numbers of type II AECs, α-smooth muscle actin+ mesenchymal cells,
          collagen deposition, and accumulation of senescence-associated β-galactosidase+ lung epithelial
          cells.
        explanation: >-
          Prolonged epithelial shelterin deletion produces spontaneous remodeling without bleomycin.
- name: AT2-specific Sin3a conditional loss
  species: Mus musculus
  genotype: Conditional Sin3a loss in adult Sftpc-expressing AT2 cells
  description: >-
    Induced p53-dependent AT2 senescence produces progressive fibrosis; comparison with conditional AT2
    ablation distinguishes senescence from simple cell loss.
  publication: PMID:32991815
  evidence:
  - reference: PMID:32991815
    reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent
      cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis.
    explanation: >-
      An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin;
      it does not establish immune independence or the initiating lesion in all human IPF.
  notes: >-
    Erratum PMID:34256008 corrects figure alignment, panel labels and the comparator mouse line to RosaDTA;
    it does not withdraw the spontaneous-fibrosis result.
  modeled_mechanisms:
  - target: AT2 cell senescence and SASP
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Conditional Sin3a loss induces p53-dependent senescence, AT2 depletion and spontaneous fibrosis.
    limitations: >-
      Engineered Sin3a loss establishes mechanistic sufficiency in mice, not a common human initiating
      lesion.
    evidence:
    - reference: PMID:32991815
      reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent
        cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis.
      explanation: >-
        An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin;
        it does not establish immune independence or the initiating lesion in all human IPF.
    readouts:
    - name: AT2 senescence and progressive fibrosis
      target: AT2 cell senescence and SASP
      direction: INCREASED
      interpretation: >-
        Conditional Sin3a loss induces p53-dependent senescence, AT2 depletion and spontaneous fibrosis.
      evidence:
      - reference: PMID:32991815
        reference_title: Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent
          cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis.
        explanation: >-
          An AT2-directed genetic perturbation produces spontaneous progressive fibrosis without bleomycin;
          it does not establish immune independence or the initiating lesion in all human IPF.
- name: AT2-specific TERT conditional deletion with bleomycin
  species: Mus musculus
  genotype: SPC-Tert conditional knockout
  description: >-
    TERT deletion alone did not cause fibrosis over 9 months, but increased injury-associated senescence
    and fibrosis after bleomycin without a significant effect on measured AT2 telomere length.
  publication: PMID:31000627
  evidence:
  - reference: PMID:31000627
    reference_title: Telomerase reverse transcriptase ameliorates lung fibrosis by protecting alveolar epithelial cells against senescence.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis
      compared with control mice, accompanied by increased pro-fibrogenic cytokine expression but without
      a significant effect on AECII telomere length.
    explanation: >-
      TERT loss amplifies injury-associated fibrosis without measurable telomere shortening in this model.
  modeled_mechanisms:
  - target: AT2 cell senescence and SASP
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      TERT deficiency heightens senescence and impairs regeneration after injury.
    limitations: >-
      This is a TERT-function perturbation with a second-hit requirement, not interchangeable evidence
      for telomere shortening.
    evidence:
    - reference: PMID:31000627
      reference_title: Telomerase reverse transcriptase ameliorates lung fibrosis by protecting alveolar epithelial cells against senescence.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis
        compared with control mice, accompanied by increased pro-fibrogenic cytokine expression but without
        a significant effect on AECII telomere length.
      explanation: >-
        TERT loss amplifies injury-associated fibrosis without measurable telomere shortening in this
        model.
    readouts:
    - name: Injury-associated fibrosis and cytokine expression
      target: AT2 cell senescence and SASP
      direction: INCREASED
      interpretation: >-
        TERT deficiency heightens senescence and impairs regeneration after injury.
      evidence:
      - reference: PMID:31000627
        reference_title: Telomerase reverse transcriptase ameliorates lung fibrosis by protecting alveolar epithelial cells against senescence.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          However, upon bleomycin treatment, they exhibited enhanced lung injury, inflammation, and fibrosis
          compared with control mice, accompanied by increased pro-fibrogenic cytokine expression but
          without a significant effect on AECII telomere length.
        explanation: >-
          TERT loss amplifies injury-associated fibrosis without measurable telomere shortening in this
          model.
inheritance:
- name: Autosomal dominant predisposition in a molecularly defined subset
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Some familial cases have heterozygous pathogenic variants with age-dependent incomplete penetrance
    and variable ILD phenotype. Most IPF does not follow a single Mendelian pattern. Short telomeres can
    also be inherited without the familial variant, complicating recurrence prediction.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1230/
    reference_title: Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with a ... associated with predisposition to pulmonary fibrosis has
      a 50% chance of inheriting the pathogenic variant.
    explanation: >-
      The recurrence statement applies to autosomal dominant monogenic predisposition, not every sporadic
      IPF case; inheritance of a variant does not predict age of onset or guarantee disease.

environmental:
- name: Tobacco smoking
  exposure_term:
    preferred_term: Tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  description: Current and former smoking are associated with IPF susceptibility in independent cohorts, with dose-response evidence. A Korean claims cohort identified 25,113 incident cases among 23,242,836 participants; smoking intensity, duration and diagnostic ascertainment affect estimates. Susceptibility is not equivalent to an identified cause in every patient.
  evidence:
  - reference: PMID:34593614
    reference_title: 'Impact of smoking on the development of idiopathic pulmonary fibrosis: results from a nationwide population-based cohort study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively.
    explanation: Korean nationwide claims cohort supports temporality and an exposure association; diagnosis was based on codes and claims.
  - reference: PMID:32660982
    reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Ever smoking tobacco was associated with increased risk of IPF: OR 2.20 (95% CI 1.74 to 2.79)'
    explanation: Independent Australian case-control study included 503 cases and 902 population controls.
  influences_mechanisms:
  - target: Repetitive alveolar epithelial injury and aberrant repair
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.
    evidence:
    - reference: PMID:34593614
      reference_title: 'Impact of smoking on the development of idiopathic pulmonary fibrosis: results from a nationwide population-based cohort study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The risk of IPF was significantly higher in current and former smokers than in never smokers, with an aHR of 1.66 (95% CI 1.61 to 1.72) and 1.42 (95% CI 1.37 to 1.48), respectively.
      explanation: Korean nationwide claims cohort supports temporality and an exposure association; diagnosis was based on codes and claims.
    - reference: PMID:32660982
      reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Ever smoking tobacco was associated with increased risk of IPF: OR 2.20 (95% CI 1.74 to 2.79)'
      explanation: Independent Australian case-control study included 503 cases and 902 population controls.
- name: Occupational respirable and metal dust
  exposure_term:
    preferred_term: Occupational respirable and metal dust
    term:
      id: ECTO:7000001
      label: exposure to dust
  description: Occupational dust exposure is a susceptibility modifier, with inconsistent findings for particular materials. A 78-case Korean study associated metal dust with IPF, whereas an Australian 503-case study supported respirable dust overall but not specific organic, mineral or metal categories. Job-exposure matrices, coexposures and diagnostic differences limit mechanistic inference.
  evidence:
  - reference: PMID:28157473
    reference_title: 'Occupational exposure and idiopathic pulmonary fibrosis: a multicentre case-control study in Korea.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After adjustment for environmental and military exposures and smoking history, the OR for metal dust exposure was 4.97 (95%CI 1.36-18.17) in multiple logistic regression analysis.
    explanation: Korean matched case-control study included 78 cases and 78 controls; the interval is wide.
  - reference: PMID:32660982
    reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: However occupational exposures to other specific organic, mineral or metal dusts were not associated with IPF.
    explanation: The larger Australian study did not replicate associations with these specific dust categories.
  - reference: PMID:32660982
    reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: respirable dust (OR 1.38; 1.04 to 1.82) and asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF.
    explanation: Respirable-dust association was observed even though specific metal-dust categories were null.
  influences_mechanisms:
  - target: Repetitive alveolar epithelial injury and aberrant repair
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.
    evidence:
    - reference: PMID:28157473
      reference_title: 'Occupational exposure and idiopathic pulmonary fibrosis: a multicentre case-control study in Korea.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: After adjustment for environmental and military exposures and smoking history, the OR for metal dust exposure was 4.97 (95%CI 1.36-18.17) in multiple logistic regression analysis.
      explanation: Korean matched case-control study included 78 cases and 78 controls; the interval is wide.
    - reference: PMID:32660982
      reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: However occupational exposures to other specific organic, mineral or metal dusts were not associated with IPF.
      explanation: The larger Australian study did not replicate associations with these specific dust categories.
    - reference: PMID:32660982
      reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: respirable dust (OR 1.38; 1.04 to 1.82) and asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF.
      explanation: Respirable-dust association was observed even though specific metal-dust categories were null.
- name: Occupational wood dust
  exposure_term:
    preferred_term: Occupational wood dust
    term:
      id: ECTO:7000135
      label: exposure to wood dust
  description: Pooled observational studies associate wood-dust exposure with IPF, but smoking-adjusted estimates in an earlier meta-analysis included the null. Hardwood, softwood and job-related coexposures are not interchangeable. This is an uncertain susceptibility association rather than a sufficient cause.
  evidence:
  - reference: PMID:38096107
    reference_title: 'The Impact of Occupational Exposures on the Risk of Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust.
    explanation: Meta-analysis reports pooled associations; attributable fractions rely on causal assumptions and are not demonstrated prevention effects.
  - reference: PMID:36253946
    reference_title: 'Idiopathic Pulmonary Fibrosis: What do we Know about the Role of Occupational and Environmental Determinants? A Systematic Literature Review and Meta-Analysis.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: 'Smoking adjustments: general dust (1.45 (1.04-2.03)/organic dust (2.5 (1.49-4.22)/metals (1.87 (1.16-3)/wood dust OR: 1.16 (0.86-1.61)/pesticide exposure 2.4 (0.84-6.9) were calculated.'
    explanation: Smoking-adjusted analysis in an earlier meta-analysis was compatible with no wood-dust association, limiting certainty.
  influences_mechanisms:
  - target: Repetitive alveolar epithelial injury and aberrant repair
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.
    evidence:
    - reference: PMID:38096107
      reference_title: 'The Impact of Occupational Exposures on the Risk of Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust.
      explanation: Meta-analysis reports pooled associations; attributable fractions rely on causal assumptions and are not demonstrated prevention effects.
    - reference: PMID:36253946
      reference_title: 'Idiopathic Pulmonary Fibrosis: What do we Know about the Role of Occupational and Environmental Determinants? A Systematic Literature Review and Meta-Analysis.'
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: 'Smoking adjustments: general dust (1.45 (1.04-2.03)/organic dust (2.5 (1.49-4.22)/metals (1.87 (1.16-3)/wood dust OR: 1.16 (0.86-1.61)/pesticide exposure 2.4 (0.84-6.9) were calculated.'
      explanation: Smoking-adjusted analysis in an earlier meta-analysis was compatible with no wood-dust association, limiting certainty.
- name: Occupational asbestos exposure
  exposure_term:
    preferred_term: Occupational asbestos exposure
    term:
      id: ECTO:9000033
      label: exposure to asbestos
  description: An Australian IPF case-control study reported an asbestos-exposure association. Exposure history should trigger evaluation for asbestosis; disease attributable to asbestos is classified separately from IPF. Residual diagnostic misclassification and unmeasured cumulative exposure can contribute to the epidemiologic signal.
  evidence:
  - reference: PMID:32660982
    reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF.
    explanation: Reported association concerns patients classified as IPF; it does not erase the separate diagnosis of asbestosis.
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).
    explanation: Clinically established exposure-caused ILD must be excluded before assigning IPF.
  influences_mechanisms:
  - target: Repetitive alveolar epithelial injury and aberrant repair
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.
    evidence:
    - reference: PMID:32660982
      reference_title: 'Occupational and environmental risk factors for idiopathic pulmonary fibrosis in Australia: case-control study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: asbestos (OR 1.57; 1.15 to 2.15) were independently associated with increased risk of IPF.
      explanation: Reported association concerns patients classified as IPF; it does not erase the separate diagnosis of asbestosis.
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Exclusion of other known causes of ILD (e.g., domestic and occupational environmental exposures, connective tissue disease, and drug toxicity).
      explanation: Clinically established exposure-caused ILD must be excluded before assigning IPF.
- name: Occupational agricultural dust
  exposure_term:
    preferred_term: Occupational agricultural dust
    term:
      id: ECTO:7000001
      label: exposure to dust
  description: Meta-analysis associates agricultural-dust exposure with IPF susceptibility, but jobs can combine organic antigens, mineral dust, pesticides and other agents. Established fibrotic hypersensitivity pneumonitis and pneumoconioses must be excluded; these associations do not justify reclassifying those diseases as IPF.
  evidence:
  - reference: PMID:38096107
    reference_title: 'The Impact of Occupational Exposures on the Risk of Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust.
    explanation: Pooled occupational associations include agricultural dust, with heterogeneity in exposure assessment and disease definition.
  - reference: PMID:21471066
    reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis).
    explanation: Antigen-mediated hypersensitivity pneumonitis is a distinct cause of fibrosis, even with a UIP pattern.
  influences_mechanisms:
  - target: Repetitive alveolar epithelial injury and aberrant repair
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Exposure-associated susceptibility is placed upstream of abnormal alveolar repair. The epidemiologic studies do not isolate the cellular mediators, establish sufficiency, or show that exposure removal reverses established IPF.
    evidence:
    - reference: PMID:38096107
      reference_title: 'The Impact of Occupational Exposures on the Risk of Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: ORs and PAFs, respectively, were found to be 1.6 and 7% for metal dust, 1.6 and 3% for wood dust, 1.8 and 14% for agricultural dust, and 1.8 and 4% for silica dust.
      explanation: Pooled occupational associations include agricultural dust, with heterogeneity in exposure assessment and disease definition.
    - reference: PMID:21471066
      reference_title: 'An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The major differential diagnostic considerations include UIP in other clinical settings such as connective tissue diseases, chronic hypersensitivity pneumonitis (extrinsic allergic alveolitis), and pneumoconioses (especially asbestosis).
      explanation: Antigen-mediated hypersensitivity pneumonitis is a distinct cause of fibrosis, even with a UIP pattern.

📚

References & Deep Research

References

2

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf

https://www.ncbi.nlm.nih.gov/books/NBK1230/pdf/Bookshelf_NBK1230.pdf

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/books/NBK1230/

Pulmonary Fibrosis Predisposition Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Idiopathic Pulmonary Fibrosis. Core disease mechanisms, molecular and cell...

Asta Scientific Corpus Retrieval 18 citations 2026-04-11T11:19:01.686115

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Idiopathic Pulmonary Fibrosis. Core disease mechanisms, molecular and cell...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 18
Snippets retrieved: 20

Relevant Papers

[1] Comorbidity of Pulmonary Fibrosis and COPD/Emphysema: Research Status, Trends, and Future Directions --------- A Bibliometric Analysis from 2004 to 2023

Authors: H. Fang, Tairan Dong, Zhuojun Han, Shanlin Li, Mingfei Liu et al.
Year: 2023
Venue: International Journal of Chronic Obstructive Pulmonary Disease
URL: https://www.semanticscholar.org/paper/e9e39dadd7fb76d988cbc101b957517276f55d7f
DOI: 10.2147/COPD.S426763
PMID: 37720874
PMCID: 10505036
Citations: 4
Summary: The research hotspots and trends identified in this study provide a reference for in-depth research in this field, aiming to promote the development of the comorbidity of pulmonary fibrosis and COPD/emphysema.
Evidence snippets:
Snippet 1 (score: 0.701) > Cluster #0 explores clinical conditions associated with pulmonary fibrosis, including idiopathic interstitial pneumonia, idiopathic fibrosis, and pulmonary fibrosis combined with emphysema. This cluster establishes more precise classification and diagnostic criteria for these conditions, distinguishing them from one another, and emphasizes the necessity of actively pursuing accurate diagnosis and treatment strategies in clinical research. 1][22][23] Cluster #1 primarily focuses on the latest clinical research concerning idiopathic pulmonary fibrosis, encompassing clinical classification, diagnostic criteria, cutting-edge methodologies, the influence of comorbidities on disease progression, and the effectiveness of various drug treatment modalities. ][26][27] The following clusters are dedicated to studying the pathogenesis of related diseases, including idiopathic fibrosis, by investigating genes, signaling pathways, cellular mechanisms, and more. Cluster #2 focuses on elucidating the mechanisms of cellular senescence in idiopathic fibrosis. Lung senescence, characterized by an increased number of senescent cells, is believed to directly contribute to various age-related respiratory diseases. Targeting cellular senescence through therapeutic interventions could potentially delay or even reverse age-related respiratory diseases. 9][30] Cluster #3 primarily engages in fundamental research on the cellular and molecular mechanisms underlying pulmonary fibrosis. It investigates related genes, regulatory factors, and cellular pathways to gain a deeper understanding of the pathogenic mechanisms of this disease. ][33][34] Cluster #7 delves into the intricate cellular and molecular mechanisms underlying pulmonary fibrosis. It focuses on tissue remodeling, structural alterations in fibrotic lesions, and aberrant cell populations. 6][37][38] Cluster #8 explores the cellular and molecular mechanisms of lung tissue and their implications for treatments. It demonstrates that age-related lung diseases share common mechanisms, such as telomere shortening, abnormal tissue remodeling, and functional damage. 0][41] Cluster #9 investigates the crucial role of Redox regulatory proteins, oxidative stress, and inflammatory response in the pathogenesis of pulmonary diseases, including pulmonary fibrosis.

[2] The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery

Authors: Emanuel Kolanko, Anna Cargnoni, Andrea Papait, A. Silini, P. Czekaj et al.
Year: 2024
Venue: European Respiratory Review
URL: https://www.semanticscholar.org/paper/b4406eb865ebf9edad815c6b363dbb5ace4f8679
DOI: 10.1183/16000617.0127-2023
PMID: 38232990
PMCID: 10792439
Citations: 32
Summary: In vitro lung fibrosis models have progressively improved to represent tools closely mimicking pathological processes and allow advancements of personalised medicine and enhance comprehension of pathogenic molecular mechanisms.
Evidence snippets:
Snippet 1 (score: 0.550) > Lung fibrosis is a complex process, with unknown underlying mechanisms, involving various triggers, diseases and stimuli. Different cell types (epithelial cells, endothelial cells, fibroblasts and macrophages) interact dynamically through multiple signalling pathways, including biochemical/molecular and mechanical signals, such as stiffness, affecting cell function and differentiation. Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing interstitial lung disease (fILD), characterised by a notably high mortality. Unfortunately, effective treatments for advanced fILD, and especially IPF and non-IPF progressive fibrosing phenotype ILD, are still lacking. The development of pharmacological therapies faces challenges due to limited knowledge of fibrosis pathogenesis and the absence of pre-clinical models accurately representing the complex features of the disease. To address these challenges, new model systems have been developed to enhance the translatability of preclinical drug testing and bridge the gap to human clinical trials. The use of two- and three-dimensional in vitro cultures derived from healthy or diseased individuals allows for a better understanding of the underlying mechanisms responsible for lung fibrosis. Additionally, microfluidics systems, which replicate the respiratory system's physiology ex vivo, offer promising opportunities for the development of effective therapies, especially for IPF. Tweetable abstract In vitro lung fibrosis models have progressively improved to represent tools closely mimicking pathological processes and allow advancements of personalised medicine and enhance comprehension of pathogenic molecular mechanisms. https://bit.ly/40P8gqw
Snippet 2 (score: 0.510) > Additionally, there are transgenic models in which specific gene mutations associated with ILD, such as a mutant surfactant protein C gene (SFTPC) in alveolar type II (AT2) cells [16], are triggered to induce the development of pulmonary fibrosis. In addition, the bleomycin-induced pulmonary fibrosis model is widely used and well characterised [17]. This model has proven valuable in the exploration of novel pathogenic mechanisms that may have relevance to human disease. Notably, recent research has demonstrated the pivotal role of RNA-binding motif protein 7 (RBM7) in fibrosis onset [18]. Nevertheless, these models present notable limitations [19], possibly for the fact that all animal models of IPF are artificially induced using single agents or target a single cell type, while it is well known that the pathogenesis is multifactorial and still remains elusive. > In this context, in vitro models, despite being a simplified representation of actual diseased tissue, can be valuable because they allow for the identification of specific cellular and molecular mechanisms that trigger and induce disease progression. > Nonetheless, as they continue to evolve, in vitro models are increasingly approaching the complexity of in vivo systems. For example, lung organoids derived from induced pluripotent stem cells (iPSCs) obtained from patients enable monitoring of the alterations acquired by the different cell populations during the disease progression. This approach aids in pinpointing the specific states of maturation where issues may arise. Moreover, the use of human material, with a personalised medicine perspective, enables the screening of drugs, including off-label drugs, for drug repurposing. In recent years, in vitro models have been developed to improve preclinical drug testing and bridge the translational gap to human clinical trials. These techniques offer advanced imaging and analysis of disease mechanisms, allowing for drug discovery and validation in a personalised manner (figure 2 and table 1). This is a comprehensive overview of the various in vitro models that are accessible for studying the molecular mechanisms underlying fibrosis pathogenesis, as well as their applications in drug screening.

[3] Cellular Senescence in Lung Fibrosis

Authors: Fernanda Hernández-González, R. Faner, M. Rojas, A. Agustí, M. Serrano et al.
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/072814da23bd69a06a991e6dce8d86d029925578
DOI: 10.3390/ijms22137012
PMID: 34209809
PMCID: 8267738
Citations: 61
Influential citations: 1
Summary: Current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence are highlighted, and the idea that it also drives degenerative processes such as lung fibrosis is strengthened.
Evidence snippets:
Snippet 1 (score: 0.549) > For several decades, understanding lung fibrosis as a process that limits lifespan has challenged scientists. Progressive loss of lung function due to pulmonary fibrosis contributes significantly to the ever-increasing burden of chronic disease throughout the world. Around half of deaths in the developed world are attributable to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), the most common fibrotic interstitial lung disease (ILD) characterized by progressive and irreversible respiratory failure and death [1,2]. The phenomenological complexity existing in the lung fibrosis process has led, over the years, to a rising number of hypotheses about the specific cellular and molecular causes. The most prominent feature of lung fibrosis is a gradual age-related loss of function that occurs at the molecular, cellular, and tissue levels. The lack of somatic maintenance and repair functions and the stochastic enforcement of damage may explain the marked variability of cellular mechanisms that appear to be involved in aging phenotypes, such as lung fibrosis [3,4]. > Fibrosis and wound healing are essentially interwoven processes, driven by a cascade of injury, inflammation, fibroblast proliferation and migration, matrix deposition and remodelling. Pathological fibrogenesis that occurs in many diverse organs and diseases is a dynamic process involving complex interactions between epithelial cells, fibroblasts, immune cells (macrophages, T-cells), and/or endothelial injuries [5,6]. There are many extrinsic hazards known to induce injury to lung epithelium-infections, exposures to organic or inorganic components, cigarette smoking, and so forth-while there is also damage of unknown aetiology. As a response to lung injury, many interrelated woundhealing pathways are activated in order to facilitate the repair, turnover, and adaptation of lung tissue [7]. However, although their aetiology and causative mechanisms varies, the different fibrotic lung diseases all fail to properly eliminate inciting factors, leading to continued tissue damaging with an abnormal and exaggerated accumulation of extracellular matrix (ECM) components and collagen deposition.

[4] Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

Authors: T. Phan, P. Paliogiannis, Gheyath K Nasrallah, Roberta Giordo, A. Eid et al.
Year: 2020
Venue: Cellular and Molecular Life Sciences: CMLS
URL: https://www.semanticscholar.org/paper/60ab2fce378cefe715daabd6fdd84f8a31c65c7a
DOI: 10.1007/s00018-020-03693-7
PMID: 33201251
PMCID: 7669490
Citations: 269
Influential citations: 9
Summary: An update is provided regarding the emerging cellular and molecular mechanisms involved in the onset and progression of idiopathic pulmonary fibrosis.
Evidence snippets:
Snippet 1 (score: 0.548) > Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.
Snippet 2 (score: 0.530) > Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is an irreversibly progressive and usually lethal disease. IPF patients typically succumb to respiratory failure secondary to loss of respiratory function from extensive fibrotic scarring of the lung parenchyma. Following diagnosis, the average life expectancy is 3-5 years. IPF is more common in males and individuals older than 60 years. The histopathological hallmarks include subpleural fibrosis, subepithelial fibroblastic foci, and microscopic honeycombing [1][2][3][4]. The clinical progress is usually complicated by acute episodes of respiratory function deterioration, termed IPF exacerbations. No effective treatments are available in preventing and controlling the acute exacerbations of IPF [5,6]. The most common complications of IPF include lung cancer, depression, pulmonary hypertension, muscle weakness, heart failure, thrombosis, acute respiratory distress syndrome (ARDS), and respiratory failure. The recent introduction of two anti-fibrotic drugs, pirfenidone and nintedanib, will likely lead to a significant retardation in lung-function decline and a reduction in the incidence and severity of associated complications. However, as these agents are not curative, new therapeutic approaches are needed [7] Given that the exact pathophysiological mechanisms involved in IPF remain elusive. Additional studies on the cellular processes and molecular pathways involved are essential for the development of effective IPF therapies. A number of processes and factors, such as the role of aging and cellular apoptosis, oxidative stress, endoplasmic reticulum stress, cellular plasticity, and noncoding RNAs are the focus of intense research. Their better understanding might lead to the effective modulation of aberrant cellular processes and the maintenance of tissue homeostasis in the lung. This review discusses the key evolving concepts in IPF pathogenesis, the cellular and molecular mechanisms involved in the onset and progression of the disease, and the identification and development of novel targeted therapies.

[5] Targeting Chitinase 1 and Chitinase 3-Like 1 as Novel Therapeutic Strategy of Pulmonary Fibrosis

Authors: S. Lee, Chang-min Lee, B. Ma, Suchitra Kamle, J. Elias et al.
Year: 2022
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/8cc7e64fb666492633849749ee3952faf632dac9
DOI: 10.3389/fphar.2022.826471
PMID: 35370755
PMCID: 8969576
Citations: 20
Summary: Specific roles and regulatory mechanisms of CHIT1 and CHI3L1 in profibrotic cell and tissue responses as novel therapeutic targets of pulmonary fibrosis are discussed.
Evidence snippets:
Snippet 1 (score: 0.541) > Tissue fibrosis is a major cause of morbidity in pulmonary fibrosis. As a normal repair response, fibrosis is a series of process of cellular damage caused by various conditions that initiate inflammation, recruitments of inflammatory cells, followed by final tissue repair and termination of inflammation. Loss of regulatory signals and imbalance in the process of wound healing leads to aberrant activation of repair response, causing pathologic fibrosis in various organs including lung, resulting in a disease state (Wilson and Wynn, 2009). Since excellent review articles detailing the molecules and signaling pathways involved in the pathogenesis of pulmonary fibrosis are already available (Micallef et al., 2012;Wolters et al., 2014;Sgalla et al., 2018;Strykowski and Adegunsoye, 2021), in this section, we only focus on the discussion of major factors leading to pathologic fibrosis, that can be also regulated by CHIT1 or CHI3L1 in the development and progression of pulmonary fibrosis. Pulmonary fibrosis comprises a number of different etiologies and pathologies with completely different clinical features and therapeutic responses. Accordingly, there are significant limitations in identifying common pathogenetic mechanisms of pulmonary fibrosis. This is particularly true for in vitro cell or in vivo preclinical animal models of pulmonary fibrosis, since currently no preclinical models are exactly representing the characteristic cellular and tissue responses of IPF and other interstitial lung disease (ILD). In addition, so far relatively small number of human studies with dysregulated expression of CHIT1 and/or CHI3L1 in the patients with IPF and ILD add certain limitations in direct clinical translation of preclinical data. With these limitations in mind, here the molecular and mechanistic implications of CHIT1 and CHI3L1 as potential therapeutic targets are discussed based on up-to-dated and common lung pathologies of pulmonary fibrosis.

[6] Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review

Authors: Darya Enzel, M. Kriventsov, T. Sataieva, V. Malygina
Year: 2024
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/fc44de05d17a984b1918bf7d7db585d16b6dc7dd
DOI: 10.3390/ijms25168946
PMID: 39201632
PMCID: 11355055
Citations: 6
Summary: This literature review presents the key modern concepts concerning molecular genetics and cellular mechanisms of lung fibrosis development, based mainly on in vitro and in vivo studies in experimental models of bleomycin-induced pulmonary fibrosis, as well as the latest data on metabolic features, potential targets, and effects of vitamin D and its metabolites.
Evidence snippets:
Snippet 1 (score: 0.526) > Idiopathic pulmonary fibrosis remains a relevant problem of the healthcare system with an unfavorable prognosis for patients due to progressive fibrous remodeling of the pulmonary parenchyma. Starting with the damage of the epithelial lining of alveoli, pulmonary fibrosis is implemented through a cascade of complex mechanisms, the crucial of which is the TGF-β/SMAD-mediated pathway, involving various cell populations. Considering that a number of the available drugs (pirfenidone and nintedanib) have only limited effectiveness in slowing the progression of fibrosis, the search and justification of new approaches aimed at regulating the immune response, cellular aging processes, programmed cell death, and transdifferentiation of cell populations remains relevant. This literature review presents the key modern concepts concerning molecular genetics and cellular mechanisms of lung fibrosis development, based mainly on in vitro and in vivo studies in experimental models of bleomycin-induced pulmonary fibrosis, as well as the latest data on metabolic features, potential targets, and effects of vitamin D and its metabolites.

[7] Translational control of the fibroblast-extracellular matrix association

Authors: R. Nho, V. Polunovsky
Year: 2013
Venue: Translation
URL: https://www.semanticscholar.org/paper/9761d71436d581f1a9fae8de80d2a797b79bf162
DOI: 10.4161/trla.23934
PMID: 26824013
PMCID: 4718055
Citations: 10
Summary: Evidence is presented indicating that the dysregulation of the eIF4F-mediated translational apparatus is an important factor in the development and progression of IPF and other fibrotic disorders.
Evidence snippets:
Snippet 1 (score: 0.524) > Pulmonary fibrosis can be a complication of a group of lung disorders called interstitial lung diseases (ILDs). 1 In cases when pulmonary fibrosis develops within the lung in the absence of any known provocations, it is termed idiopathic pulmonary fibrosis (IPF), which is also known as cryptogenic fibrosing alveolitis (CFA). IPF is characterized by abnormal expansion of granulation tissue due to excessive production of ECM, hyperpropagation of stromal fibroblasts and vast scarring of normal lung parenchyma leading to a deficiency in gas exchange. IPF is usually fatal with life expectance within 2 to 6 y following diagnosis. 2 Although there has been some progress in understanding the pathogenesis of IPF, there is still no proven effective therapy Pulmonary fibrosis is a severe lung disease characterized by sustained propagation of lung fibroblasts and relentless accumulation of extracellular matrix (ECM). Idiopathic pulmonary fibrosis (IPF) is the most severe chronic form of pulmonary fibrosis and results both in the gradual exchange of normal lung parenchyma with fibrotic tissue and in the irreversible impairment of gas exchange in the lung. Despite the urgency for novel therapies in IPF treatment, there is no effective and proven medical therapy available. Molecular mechanisms underlying IPF pathogenesis include aberrant ECM signaling through the canonical integrin/PI3K/Akt/ mTORC1 signal transduction pathway. One important and well-characterized downstream effector of this pathway is the cellular protein synthesis machinery. Here we will review the recent advances in our understanding of the function of ECM and integrin receptor signaling in development of IPF and will present evidence indicating that the dysregulation of the eIF4F-mediated translational apparatus is an important factor in the development and progression of IPF and other fibrotic disorders. We further discuss the perspectives and challenges to curbing this deadly disease by targeting aberrant translation. > available and lung transplantation is the only viable intervention in end-stage disease.

[8] Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Authors: V. Suryadevara, R. Ramchandran, D. Kamp, V. Natarajan
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/9ad48e612a124c8c4940043f4bae96946d26afc7
DOI: 10.3390/ijms21124257
PMID: 32549377
PMCID: 7352853
Citations: 108
Influential citations: 5
Summary: The current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipid metabolism and their metabolizing enzymes in the development of lung fibrosis is described.
Evidence snippets:
Snippet 1 (score: 0.523) > Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

[9] Molecular pathways in idiopathic pulmonary fibrosis pathogenesis: Transcending barriers to optimally targeted pharmacotherapies

Authors: R. Strykowski, A. Adegunsoye
Year: 2021
Venue: EBioMedicine
URL: https://www.semanticscholar.org/paper/3f70120771654984a132710d119c3cee6849ff0b
DOI: 10.1016/j.ebiom.2021.103373
PMID: 33965873
PMCID: 8114113
Citations: 1
Summary: An array of mechanisms involved in the pathophysiologic progression of previously normal lung tissue to fibrosis in IPF are examined, linking the molecular and cellular events associated with this complex disease.
Evidence snippets:
Snippet 1 (score: 0.519) > Although the survival of patients with idiopathic pulmonary fibrosis (IPF) still hovers around a median of two to five years, [1] the therapeutic landscape of this devastating interstitial lung disease is encumbered by a paucity of effective pharmacotherapies. Widely used anti-fibrotic medications slow the rate of functional decline [2,3] but are often associated with adverse effects and persistently high symptom burden. As the pathophysiologic mechanisms underlying fibrosis are yet to be fully elucidated, our understanding of disease progression in IPF remains stifled, posing substantial limitations to the potential value that could be gained from more novel therapies targeting these mechanisms. Prior genome-wide associated studies evaluating the genetic profiles of affected patients have identified several notable variants and risk polymorphisms associated with IPF pathogenesis. [4] Likewise, recent epigenomic, transcriptomic, and proteomic data have helped to generate a single-cell atlas of IPF defining key molecular factors and pathways in the progression of fibrosis. [5] Other histopathologic analyses and investigations focused on immunophenotyping have identified phenotypically distinct CD4 + T cell infiltrates within the lung tissue in patients with IPF. [6] From a macroscopic perspective, recent investigations have found a significant loss of terminal bronchioles in lung tissue obtained from patients with IPF, implicating the small airways in this disease. [7] Taken together, these underscore numerous efforts that further illuminate the pathophysiology of this complex disease, with the overall goal of identifying optimal therapeutic targets and improving currently existing ones. > In this issue of EBioMedicine, Xu and colleagues [8] examine an array of mechanisms involved in the pathophysiologic progression of previously normal lung tissue to fibrosis in IPF. [8] Their novel and exciting findings link the molecular and cellular events associated with IPF to the concomitant structural and histological events.

[10] Bleomycin-Induced Fibrosis and the Effectiveness of Centella Asiatica as a Treatment

Authors: N. Soeroso, M. Ichwan, A. S. Wahyuni, C. Mariedina, Yabestin Pakpahan
Year: 2024
Venue: Journal of Experimental Pharmacology
URL: https://www.semanticscholar.org/paper/d54d6d4e0d4a082eaac34ebd0bc406fdd20850ca
DOI: 10.2147/JEP.S463899
PMID: 39345799
PMCID: 11438459
Citations: 3
Summary: The induction of bleomycin 4 mg/kg/BB was proven to cause fibrosis in the lungs of rats, and Centella asiatica extract was used as a treatment and further research regarding antifibrotic drugs is hoped to reduce fibrotic areas significantly.
Evidence snippets:
Snippet 1 (score: 0.517) > Fibrosis is the most common interstitial lung disease defined by regular interstitial pneumonia histological pattern. 1 Idiopathic pulmonary fibrosis is a lung disorder where scar tissue is found in the lungs, however, the cause is still unknown. Pulmonary fibrosis patients may have a poor prognosis compared to other malignancies. Untreated pulmonary fibrosis can progress to CPD (Chronic Lung Disease), resulting in tissue death. 2 Data on the incidence of pulmonary fibrosis varies, in the United States, it is 6.8-8.8 per 100,000 population per year, Europe 0.22-7.4 per 10,000 population, and the incidence of fibrosis increases with age. 3,4 leomycin is a compound produced by Streptomyces verticillus bacteria, and the bacteria is often used in trial animal interventions. Bleomycin is often used in chemotherapy, but this compound has the side effect of being toxic to lung cells. The mechanism of bleomycin toxicity has been tested in vitro. Side effects of using bleomycin include nausea, fever, vomiting, and allergies. Treatment with bleomycin can also cause interstitial pneumonitis and pulmonary fibrosis. 5 nimal models are crucial to the study of disease, and lung pathobiology is studied using many different models. Over time, numerous models of pulmonary fibrosis have been created. Common techniques include silica or asbestos, radiation damage, bleomycin, transgenic mice, and gene transfer via fibrogenic cytokines. As of right now, bleomycin is the mechanism employed to cause experimental lung fibrosis in animals. 6 egrettably, lung damage resulting from pulmonary fibrosis is irreversible and permanent. The lungs may function better if the condition is identified early and treated. The majority of pulmonary fibrosis therapies aim to enhance quality of life and reduce symptoms. Lung illness fibroproliferative is common and has a high death rate. Inflammation, mesenchymal cell proliferation, and the deposition of interstitial matrix constituents including collagen and fibronectin are all involved in the pathophysiology of fibrotic lung disease.

[11] Lung regeneration: diverse cell types and the therapeutic potential

Authors: Yutian Chen, Zhen Li, Gaili Ji, Shaochi Wang, Chunheng Mo et al.
Year: 2024
Venue: MedComm
URL: https://www.semanticscholar.org/paper/0fbe00de4b129b66ffcc63fd4298d45dc0352a8c
DOI: 10.1002/mco2.494
PMID: 38405059
PMCID: 10885188
Citations: 27
Summary: A review of the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.
Evidence snippets:
Snippet 1 (score: 0.512) > Abstract Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

[12] The Mechanism of Oxidative Stress in Pulmonary Fibrosis and Research Progress

Authors: Duo Xu, Qian Wang, Meng Lyu, Chunyu Huang, Xianglin Yuan et al.
Year: 2026
Venue: Antioxidants
URL: https://www.semanticscholar.org/paper/54c6c9cba7e158d270ee82da0a58117282c8ae40
DOI: 10.3390/antiox15010142
PMID: 41596200
PMCID: 12837592
Citations: 1
Summary: This review summarizes the regulatory mechanisms of oxidative stress in pulmonary fibrosis, with a focus on its critical role in inducing and promoting fibrosis through relevant target cells and signaling pathways.
Evidence snippets:
Snippet 1 (score: 0.511) > Pulmonary fibrosis (PF) is a group of chronic progressive lung diseases characterized by irreversible remodeling of lung tissue structure, abnormal proliferation of fibroblasts, and excessive deposition of extracellular matrix (ECM), among which idiopathic pulmonary fibrosis (IPF) is the most typical subtype. Currently, the only two clinically approved therapeutic drugs (nintedanib and pirfenidone) can only partially slow disease progression without reversing fibrotic lesions, and are associated with varying degrees of adverse effects. Oxidative stress, defined as a pathological imbalance between systemic oxidant and antioxidant systems, has been substantiated by extensive research as a pivotal mechanism driving the pathogenesis and progression of pulmonary fibrosis. This review summarizes the regulatory mechanisms of oxidative stress in pulmonary fibrosis, with a focus on its critical role in inducing and promoting fibrosis through relevant target cells and signaling pathways. We also specifically highlight the latest progress and challenges in therapeutic strategies targeting oxidative stress, and discuss next-generation therapies, including the modulation of endogenous antioxidant pathways, supplementation of exogenous antioxidants, as well as nanomaterials, exosomes, and combination therapies. We hope this review will deepen the understanding of oxidative stress and pulmonary fibrosis, and provide new directions for improving the clinical efficacy of oxidative stress-targeted therapies.

[13] Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis

Authors: I. Chen, Yi-Ching Liu, Yen-Hsien Wu, S. Lo, Z. Dai et al.
Year: 2022
Venue: Cells
URL: https://www.semanticscholar.org/paper/1254ef188f65fe4aacc0fbc21eb4ea91c5256fba
DOI: 10.3390/cells11091543
PMID: 35563849
PMCID: 9099509
Citations: 12
Summary: This review summarizes the current research on proteasome inhibitors for pulmonary fibrosis, and provides a reference for whether proteasomal inhibition have the potential to become new drugs for the treatment of lung fibrosis.
Evidence snippets:
Snippet 1 (score: 0.510) > Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and usually lethal disease characterized by an abnormal fibrotic response involving large areas of the lungs. Risk factors associated with IPF include smoking, environmental factors, comorbidities, and viral infections [1]. Most patients have persistent dyspnea and limited exercise tolerance resulting in a poor quality of life. Many patients develop pulmonary hypertension and are at an increased risk of pulmonary embolism and sudden cardiac death [2]. The molecular mechanisms underlying the pathogenesis and development of IPF are unclear, however molecules including chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, and non-coding RNA, and cellular processes, including apoptosis, senescence, hypoxia, endothelial-mesenchymal transition, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and alternative polyadenylation have been linked with the development of IPF [3]. Pirfenidone and nintedanib are the mainstays of current medical treatment of IPF, however they do not completely prevent or improve lung function. It is essential to find additional drugs that can effectively reduce the pro-fibrotic maturation of lung fibroblasts, and ultimately prevent IPF progression. Understanding the molecular mechanisms of IPF will aid in drug discovery. The wound healing response induced by Intrinsic risk factors including genetic susceptibility, aging, male sex, the lung microbiome, and comorbidities have been associated with the pathogenesis of IPF [8]. The susceptibility genes associated with the pathogenesis of IPF are currently classified into four categories: (1) genes related to alveolar stability (such as SFTPC, SFTPA1, SFTPA2);

[14] Are mast cells instrumental for fibrotic diseases?

Authors: C. Overed-Sayer, L. Rapley, T. Mustelin, D. Clarke
Year: 2014
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/706efd587a7fd74ae41d832bf0427b99755c3ea9
DOI: 10.3389/fphar.2013.00174
PMID: 24478701
PMCID: 3896884
Citations: 98
Influential citations: 6
Summary: The mast cell is discussed and its physiological role in tissue repair and remodeling, as well as its pathological role in fibrotic diseases such as IPF, where the process of tissue repairand remodeling is thought to be dysregulated.
Evidence snippets:
Snippet 1 (score: 0.505) > Idiopathic pulmonary fibrosis is a devastating disease for the patient. There is currently no effective treatment for this disease and the prognosis is bleak. As the term "idiopathic" indicates, the causes of the disease are unknown, as are the molecular mechanisms underpinning initiation and progression of the condition. Clearly, fibrotic processes play a key role in driving the relentless destruction of alveolar integrity, resulting eventually in a declining ability of the lung to oxygenate the blood. This decline is the root cause of the deteriorating health of the patient once the disease passes from its typically undiagnosed, early phase, into its clinically symptomatic phase. Within less than 3 years in most patients have lost much of their respiratory capacity and require drastic measures to survive. > The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for IPF, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of IPF. > On the positive side, with emerging new insights into the pathways and cell types involved in IPF come new opportunities for therapeutic intervention. Technologies for molecular profiling of patient tissue samples are already revealing many hitherto unexpected aspects of the disease pathology. Several new cell types, including the myofibroblast and the mast cell, offer therapeutic possibilities not previously exploited. However, the only conclusive way to determine if these cells are important for the pathogenesis of IPF is to target them with sufficiently powerful therapeutics and determine the impact on disease progression in phase 2 clinical trials. Another potentially helpful way to success may be that new therapeutics are first tested in other fibrotic conditions than IPF. Based on our current understanding of disease mechanisms, it appears likely that therapeutic interventions that are efficacious in one form of fibrotic disease will be efficacious in other fibrotic conditions. Thus, the clinically most feasible disease indication may serve as a first read-out to support the testing in more challenging indications, such as IPF. This may well be the case for mast cell-targeted therapies.

[15] The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

Authors: S. Kim, P. Cheresh, R. Jablonski, David B. Williams, D. Kamp
Year: 2015
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/2928a04f743ee87fdaa9439048757c7aa1d89ea3
DOI: 10.3390/ijms160921486
PMID: 26370974
PMCID: 4613264
Citations: 111
Influential citations: 3
Summary: A conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function is presented and suggests novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer.
Evidence snippets:
Snippet 1 (score: 0.502) > Pulmonary fibrosis is characterized by an over abundant accumulation of extracellular matrix (ECM) collagen deposition in the distal lung interstitial tissue in association with an injured overlying epithelium and activated myofibroblasts. Idiopathic pulmonary fibrosis (IPF) is the most common variety of lung fibrosis and carries a sobering mortality approaching 50% at 3-4 years [1]. Although many of the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis have emerged from numerous studies over the past several decades, the precise pathways involved, their regulation, and the role of crosstalk between cells are not fully understood. With the exception of two FDA-approved drug therapies (pirfenidone and nintenanib) emerging in the fall of 2014, there are no effective therapies for patients with IPF. Furthermore, these two drugs primarily slow disease progression rather than improve lung function or symptoms. A better understanding of the pathobiology of pulmonary fibrosis is critically important in the design of more useful therapies. > As will be reviewed herein, the extent of alveolar epithelial cell (AEC) injury, repair, and aging are emerging as critical determinants underlying pulmonary fibrosis. The purpose of this review is to highlight our current understanding of the causal role of AEC mitochondrial DNA (mtDNA) damage following oxidative stress in promoting AEC apoptosis and pulmonary fibrosis. Although oxidative mtDNA damage in other cell types (i.e., vascular endothelial cells, macrophages, fibroblasts, etc.) are likely important, we concentrate on the lung epithelium given its prominent role in the pathophysiology of lung fibrosis. In particular, we focus on asbestosis (pulmonary fibrosis arising following asbestos exposure) as it shares radiographic and pathologic features with IPF though IPF is more common and carries a worse prognosis. Our group is using the asbestos paradigm to better understand the pathophysiologic mechanisms underlying pulmonary fibrosis.

[16] Genome-Wide Transcriptional Response During the Development of Bleomycin-Induced Pulmonary Fibrosis in Sprague-Dawley Rats

Authors: Han-Jin Park, Mi-Jin Yang, Jung-Hwa Oh, Young-Su Yang, M. Kwon et al.
Year: 2010
Venue: Toxicological Research
URL: https://www.semanticscholar.org/paper/6c1484630c31abb392dd75998dcdefd244abf882
DOI: 10.5487/TR.2010.26.2.137
PMID: 24278517
PMCID: 3834473
Citations: 5
Influential citations: 1
Summary: Global gene expression analysis revealed significantly altered expression of genes in a time-dependent manner during the development of pulmonary fibrosis, and the expression of triggering receptor expressed on myeloid cells 2, secreted phosphoprotein 1, and several proteases was considerably induced in the lung after bleomycin treatment.
Evidence snippets:
Snippet 1 (score: 0.501) > Idiopathic pulmonary fibrosis is a consequence of abnormal tissue repair, which is characterized by extensive inflammation in the interstitial and alveolar spaces, proliferation of fibroblasts, and progressive fibrosis leading to the destruction of lung function (Selman et al., 2004). Pulmonary fibrosis involves cytokine networks and cellular interactions among several cell types, which results in increased collagen gene expression and collagen deposition in the lungs (Piguet et al., 1990;. Despite many investigations on the pathogenesis of pulmonary fibrosis and its relationship to immune cells, extracellular matrix repair, cytokines, and chemokines, the molecular mechanisms underlying this disease remain unclear (Zhang et al., 1994(Zhang et al., , 1996Kuwano et al., 2001;Gharaee-kermani et al., 2008). > Bleomycin is a useful chemotherapeutic antitumor drug, derived from Streptomyces verticillus; however, as a side effect, bleomycin treatment may lead to pulmonary fibrosis in humans and animals. Therefore, animal models of pulmonary fibrosis induced by the intratracheal instillation of bleomycin have been well established and widely used for studying the mechanisms underlying fibrosis and potential therapeutic agents (Jordana et al., 1988;Sakanashi et al., 1994;Moeller et al., 2008). Several studies using microarrays have been performed to evaluate gene expression patterns in the lungs after bleomycin instillation and identify the major genes involved in the progression of pulmonary fibrosis (Kaminski et al., 2000;Zuo et al., 2002;Katsuma et al., 2001;Pottier et al., 2007). These studies have provided information about genes that play central roles in the progression of fibrosis over time in a mouse model. Although genomic approaches using bleomycin-induced pulmonary fibrosis animal models have been useful for understanding the molecular mechanisms underlying fibrosis and for identifying fibrogenic markers, these approaches have limitations related to the vast data sets generated and the difficulty of replicating progressive fibrosis in animal models. Furthermore, recent studies aimed at eluc

[17] Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis

Authors: Yue Li, Congshan Jiang, Wenhua Zhu, Shemin Lu, Hongchuan Yu et al.
Year: 2024
Venue: Science Progress
URL: https://www.semanticscholar.org/paper/db2853a4caa1beb6b56a994ba01253577a388786
DOI: 10.1177/00368504241247402
PMID: 38651330
PMCID: 11036936
Citations: 6
Summary: The research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials are reviewed.
Evidence snippets:
Snippet 1 (score: 0.501) > Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated alveolar epithelial damage leading to abnormal repair. The intercellular microenvironment is disturbed, leading to continuous activation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and ultimately fibrosis. Moreover, pulmonary fibrosis was also found as a COVID-19 complication. Currently, two drugs, pirfenidone and nintedanib, are approved for clinical therapy worldwide. However, they can merely slow the disease's progression rather than rescue it. These two drugs have other limitations, such as lack of efficacy, adverse effects, and poor pharmacokinetics. Consequently, a growing number of molecular therapies have been actively developed. Treatment options for IPF are becoming increasingly available. This article reviews the research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials. The former includes patient case/control studies, cell models, and animal models. The latter includes transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway. We mainly focused on the therapeutic targets that have not only entered clinical trials but were publicly published with their clinical outcomes. Moreover, this work provides an outlook on some promising targets for further validation of their possibilities to cure the disease. Graphical abstract Therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis.

[18] Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

Authors: Marina R. Hadjicharalambous, M. Lindsay
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/ed2b2741fecf7bc8fcb573d9a0eea180bca01326
DOI: 10.3390/ijms21020524
PMID: 31947693
PMCID: 7013390
Citations: 57
Influential citations: 1
Summary: An overview of the emerging role of long non-coding RNAs (lncRNAs) in the development of IPF is provided.
Evidence snippets:
Snippet 1 (score: 0.496) > Fibrosis is a pathophysiological condition that can affect nearly every organ in the human body where irregular and excessive accumulation of scar tissue leads to organ failure and potentially death as seen in the final stages of fibrotic diseases such as pulmonary [1], cardiac [2], nephrotic [3], and hepatic fibrosis [4]. In combination with genetic factors, tissue injuries may provoke the development of fibrosis including exposure to damaging environmental stimuli such as irritants, smoke, radiation, viral, and bacterial infections [5,6]. > Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease (ILD) which is characterized by scar tissue accumulation, and therefore thickening of the normal lung walls, leading to impaired gas exchange and restricted ventilation. IPF is a disease of unknown aetiology, which makes the development of effective drug treatments particularly challenging [5]. Nonetheless, scientists have been intensively researching the molecular and cellular mechanisms of the disease and, although the pathogenesis of IPF is still unclear, several theories regarding the pathophysiology of IPF have been proposed [7]. > As is the case with most ILDs, inflammation was initially thought to be the major player in IPF until unresponsiveness to anti-inflammatory medications prompted the re-evaluation of this idiom [8,9]. However, the presence of immune cells in IPF lungs has been a consistent pathological finding and could be important in the development of the disease [10][11][12][13][14]. The histology of fibrotic lungs also indicates irreversible accumulation of scarred tissue characterized by collagen deposition and other alterations to the extracellular matrix (ECM) which dramatically remodels the lung architecture by stiffening the distal airspaces and parenchyma [5]. It has been suggested that lung fibrosis could be provoked by a number of different cell types including epithelial cells, fibroblasts, myofibroblasts, and immune cells [1].

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References

Deep Research

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Idiopathic Pulmonary Fibrosis. Core disease mechanisms, molecular and cell...

Relevant Papers

[1] Comorbidity of Pulmonary Fibrosis and COPD/Emphysema: Research Status, Trends, and Future Directions --------- A Bibliometric Analysis from 2004 to 2023

[2] The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery

[3] Cellular Senescence in Lung Fibrosis

[4] Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis

[5] Targeting Chitinase 1 and Chitinase 3-Like 1 as Novel Therapeutic Strategy of Pulmonary Fibrosis

[6] Cellular and Molecular Genetic Mechanisms of Lung Fibrosis Development and the Role of Vitamin D: A Review

[7] Translational control of the fibroblast-extracellular matrix association

[8] Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

[9] Molecular pathways in idiopathic pulmonary fibrosis pathogenesis: Transcending barriers to optimally targeted pharmacotherapies

[10] Bleomycin-Induced Fibrosis and the Effectiveness of Centella Asiatica as a Treatment

[11] Lung regeneration: diverse cell types and the therapeutic potential

[12] The Mechanism of Oxidative Stress in Pulmonary Fibrosis and Research Progress

[13] Evaluation of Proteasome Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis

[14] Are mast cells instrumental for fibrotic diseases?

[15] The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

[16] Genome-Wide Transcriptional Response During the Development of Bleomycin-Induced Pulmonary Fibrosis in Sprague-Dawley Rats

[17] Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis

[18] Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

Notes